Substituted Fused Imidazole Derivatives, Pharmaceutical Compositions, and Methods of Use Thereof

ABSTRACT

Substituted fused imidazole derivatives, methods of their preparation, pharmaceutical compositions comprising a substituted fused imidazole derivative, and methods of use in treating inflammation are provided. The substituted fused imidazole derivatives may control the activity or the amount or both the activity and the amount of heme-oxygenase.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention provides substituted fused imidazole derivativesthat may be useful for control of an inflammatory response. In addition,the invention provides compounds, pharmaceutical compositions, andmethods of use thereof for controlling the activity or the amount, orboth the activity and the amount, of heme-oxygenase in a mammaliansubject.

Description of Related Art

Cellular damage due to oxidative stress caused by reactive oxygenspecies (ROS) has been demonstrated to be involved in the onset orprogression of various chronic diseases, e.g., cardiovascular disease,including arteriosclerosis and hypertension; diabetes and diabeticrelated complications, such as glomerular nephropathy; cerebral nervedegenerative diseases, such as Alzheimer's disease, Parkinson's disease,ALS (amyotrophic lateral sclerosis) and multiple sclerosis; asthma,chronic obstructive pulmonary disease, skin diseases, eye diseases, andcancer. Enhancing the capability of protecting from oxidative stress maybe useful in one or more of preventing these diseases, delaying theirprogress, or delaying their onset. Further, with the varied etiologyassociated with this diverse set of diseases, a general strategy tomitigate oxidative stress would be beneficial.

The basic biochemistry of a cell generates ROS, including superoxideanions, hydroxyl anions, nitric oxide, peroxynitrite, and hydrogenperoxide. All of these products serve critical cellular signaling needs,but also have deleterious effects if overproduced or left unchecked.Many disease conditions induce persistent levels of ROS that areassociated with the establishment of chronic pathophysiologic changesseen within a variety of tissues. These complications, in and ofthemselves, may be the primary drivers of disease morbidity andmortality.

Under normal physiological conditions, production of ROS arecounterbalanced by a well defined and conserved set of cellular pathwaysthat respond to, limit, and repair the damage due to ROS. This adaptiveset of genes, called the phase II system, encodes enzymes that degradeROS directly (e.g., superoxide dismutase and catalase) as well asincrease levels of a cell's endogenous antioxidant molecules, includingglutathione and bilirubin. Examples of known phase II enzymes includeglutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1(NQO1), glutamyl-cysteinyl ligase (GCL), heme oxygenase 1 (HMOX1), andthioredoxin reductase 1 (TXNRD1). A common sequence called antioxidantresponsive element (ARE) is present in a promoter of each gene of thesephase II enzymes, and its expression is induced by the transcriptionfactor Nrf2 (NF-E2 related factor 2).

Of the phase II enzyme system, HMOX1 has been found to be a keycomponent. The role of HMOX1 is to metabolize heme into bilirubin,carbon monoxide, and free iron, as a first step of a two-step process tocatabolize heme. The first, and rate-limiting reaction, is theproduction of biliverdin and carbon monoxide from heme by HMOX1. Thesecond step is the production of bilirubin from biliverdin by biliverdinreductase. Both bilirubin and carbon monoxide have been shown toscavenge ROS and to have potent anti-oxidant and anti-inflammatoryactivity. Agents that induce production of HMOX1 have been shown to havebeneficial activity in models of diabetes, cardiovascular disease,hypertension, and pulmonary function.

HMOX1 is found in the liver, kidneys, spleen, and skin, of humans andhas also been localized to specific cell types, notably fibroblasts andmacrophages. HMOX1 exists in at least three isoforms, one constitutiveand the other two inducible. Heme, heavy metal ions (e.g., tin, gold,platinum, and mercury), transition metal ions (e.g., iron, cobalt,chromium, and nickel), and electrophiles (e.g., natural products such assulforaphane and curcumin) can all induce production of HMOX1. Inductionof HMOX1 and other phase II genes are controlled by a number oftranscription factors that are responsive to heavy metals, heme, andelectrophiles. The transcription factors Nrf2, Bach1, and Maf areparticularly important in this process. In addition, there are cofactorsand regulatory molecules that are important in regulating Phase II geneinduction. These include Keap1, an adapter molecule targeting Nrf2 forubiquitination, and two mitochondrial proteins, DJ-1 and frataxin (FXN)that serve to augment Nrf2 activation in the presence of electrophiles.HMOX1 is also induced as part of a generalized stress response tostimuli such as thermal shock, oxidative stress and cytokines such asinterleukin-1 (IL-1), tumor necrosis factor and IL-6. The stressresponse is seen as beneficial in that it results in protection ofvulnerable cell enzymes from inactivation.

BRIEF SUMMARY OF INVENTION

The invention provides substituted fused imidazole derivatives ofFormula (I):

or pharmaceutically acceptable salts thereof, as described herein. Inanother aspect, the invention provides pharmaceutical compositions whichmay reduce oxidative stress and/or inflammation. In another aspect, thepresent invention provides methods for the preparation of compounds ofFormula (I) and pharmaceutically acceptable salts thereof. In anotheraspect, the invention provides pharmaceutical compositions comprising acompound of Formula (I) or a pharmaceutically acceptable salt thereof.In another aspect, the present invention provides methods of treatmentcomprising: administering to a subject a compound of Formula (I) or apharmaceutically acceptable salt thereof.

The compounds of Formula (I) and pharmaceutically acceptable saltsthereof are useful as agents that induce the production of and/orincrease the activity of HMOX1, and thus may be useful to treat variouschronic diseases that are associated, at least in part, with oxidativestress including, but not limited to: cardiovascular disease includingarteriosclerosis and hypertension; diabetes and diabetic relatedcomplications such as glomerular nephropathy; cerebral nervedegenerative diseases such as Alzheimers disease, Parkinson's disease,ALS (amyotrophic lateral sclerosis) and multiple sclerosis; asthma;chronic obstructive pulmonary disease; skin diseases; eye diseasesincluding macular degeneration, cataracts, light retinopathy, andretinopathy of prematurity; and cancer.

BRIEF DESCRIPTION OF DRAWINGS

Not applicable

DETAILED DESCRIPTION

The following definitions are intended to clarify the terms defined. Ifa particular term used herein is not specifically defined, the termshould not be considered to be indefinite. Rather, such undefined termsare to be construed in accordance with their plain and ordinary meaningto a person of ordinary skill in the field(s) of art to which theinvention is directed.

As used herein the term “alkyl” refers to a straight or branched chainsaturated hydrocarbon having one to ten carbon atoms, which may beoptionally substituted, as herein further described, with multipledegrees of substitution being allowed. Examples of “alkyl” as usedherein include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl,n-pentyl, neopentyl, n-hexyl, and 2-ethylhexyl.

The number carbon atoms in an alkyl group is represented by the phrase“C_(x-y) alkyl,” which refers to an alkyl group, as herein defined,containing from x to y, inclusive, carbon atoms. Thus, C₁₋₆ alkylrepresents an alkyl chain having from 1 to 6 carbon atoms and, forexample, includes, but is not limited to, methyl, ethyl, n-propyl,isopropyl, isobutyl, n-butyl, sec-butyl, tert-butyl, isopentyl,n-pentyl, neopentyl, and n-hexyl.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent saturated hydrocarbon radical having from one to tencarbon atoms, which may be optionally substituted as herein furtherdescribed, with multiple degrees of substitution being allowed. Examplesof “alkylene” as used herein include, but are not limited to, methylene,ethylene, n-propylene, 1-methylethylene, 2-methylethylene,dimethylmethylene, n-butylene, 1-methyl-n-propylene, and2-methyl-n-propylene.

The number of carbon atoms in an alkylene group is represented by thephrase “C_(x-y) alkylene,” which refers to an alkylene group, as hereindefined, containing from x to y, inclusive, carbon atoms. Similarterminology will apply for other terms and ranges as well. Thus, C₁₋₄alkylene represents an alkylene chain having from 1 to 4 carbons atoms,and, for example, includes, but is not limited to, methylene, ethylene,n-propylene, 1-methylethylene, 2-methylethylene, dimethylmethylene,n-butylene, 1-methyl-n-propylene, and 2-methyl-n-propylene.

As used herein, the term “cycloalkyl” refers to a saturated, three- toten-membered, cyclic hydrocarbon ring, which may be optionallysubstituted as herein further described, with multiple degrees ofsubstitution being allowed. Such “cycloalkyl” groups are monocyclic,bicyclic, or tricyclic. Examples of “cycloalkyl” groups as used hereininclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

The number of carbon atoms in a cycloalkyl group will be represented bythe phrase “C_(x-y) cycloalkyl,” which refers to a cycloalkyl group, asherein defined, containing from x to y, inclusive, carbon atoms. Similarterminology will apply for other terms and ranges as well. Thus, C₃₋₁₀cycloalkyl represents a cycloalkyl group having from 3 to 10 carbons asdescribed above, and for example, includes, but is not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,norbornyl, and adamantyl.

As used herein, the term “heterocycle” or “heterocyclyl” refers to anoptionally substituted mono- or polycyclic saturated ring systemcontaining one or more heteroatoms. Such “hetercycle” or “heterocyclyl”groups may be optionally substituted as herein further described, withmultiple degrees of substitution being allowed. The term “heterocycle”or “heterocyclyl,” as used herein, does not include ring systems thatcontain one or more aromatic rings. Examples of heteroatoms includenitrogen, oxygen, or sulfur atoms, including N-oxides, sulfur oxides,and sulfur dioxides. Typically, the ring is three- to twelve-membered.Such rings may be optionally fused to one or more of anotherheterocyclic ring(s) or cycloalkyl ring(s). Examples of “heterocyclic”groups, as used herein include, but are not limited to, tetrahydrofuran,tetrahydropyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine,morpholine, tetrahydrothiopyran, and tetrahydrothiophene, whereattachment can occur at any point on said rings, as long as attachmentis chemically feasible. Thus, for example, “morpholine” refers tomorpholin-2-yl, morpholin-3-yl, and morpholin-4-yl.

As used herein, when “heterocycle” or “heterocyclyl” is recited as apossible substituent, the “heterocycle” or “heterocyclyl” group canattach through either a carbon atom or any heteroatom, to the extentthat attachment at that point is chemically feasible. For example,“heterocyclyl” would include pyrrolidin-1-yl, pyrrolidin-2-yl, andpyrrolidin-3-yl. When “heterocycle” or “heterocyclyl” groups contain anitrogen atom in the ring, attachment through the nitrogen atom canalternatively be indicated by using an “-ino” suffix with the ring name.For example, pyrrolidino refers to pyrrolidin-1-yl.

As used herein the term “halogen” refers to fluorine, chlorine, bromine,or iodine.

As used herein, the term “oxo” refers to a >C═O substituent. When an oxosubstituent occurs on an otherwise saturated group, such as with anoxo-substituted cycloalkyl group (e.g., 3-oxo-cyclobutyl), thesubstituted group is still intended to be a saturated group.

As used herein the term “haloalkyl” refers to an alkyl group, as definedherein, that is substituted with at least one halogen. Examples ofbranched or straight chained “haloalkyl” groups as used herein include,but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, andt-butyl substituted independently with one or more halogens, forexample, fluoro, chloro, bromo, and iodo. The term “haloalkyl” should beinterpreted to include groups such as —CF₃, —CH₂—CF₃, and —CF₂Cl.

As used herein, the term “aryl” refers to a six- to ten-membered cyclic,aromatic hydrocarbon, which may be optionally substituted as hereinfurther described, with multiple degrees of substitution being allowed.Examples of “aryl” groups as used herein include, but are not limitedto, phenyl and naphthyl. As used herein, the term “aryl” also includesring systems in which a phenyl or naphthyl group is optionally fusedwith one to three non-aromatic, saturated or unsaturated, carbocyclicrings. For example, “aryl” would include ring systems such as indene,with attachment possible to either the aromatic or the non-aromaticring(s).

As used herein, the term “heteroaryl” refers to a five- tofourteen-membered optionally substituted mono- or polycyclic ringsystem, which contains at least one aromatic ring and also contains oneor more heteroatoms. Such “heteroaryl” groups may be optionallysubstituted as herein further described, with multiple degrees ofsubstitution being allowed. In a polycyclic “heteroaryl” group thatcontains at least one aromatic ring and at least one non-aromatic ring,the aromatic ring(s) need not contain a heteroatom. Thus, for example,“heteroaryl,” as used herein, would include indolinyl. Further, thepoint of attachment may be to any ring within the ring system withoutregard to whether the ring containing the attachment point is aromaticor contains a heteroatom. Thus, for example, “heteroaryl,” as usedherein, would include indolin-1-yl, indolin-3-yl, and indolin-5-yl.Examples of heteroatoms include nitrogen, oxygen, or sulfur atoms,including N-oxides, sulfur oxides, and sulfur dioxides, where feasible.Examples of “heteraryl” groups, as used herein include, but are notlimited to, furyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, isoxazolyl, isothiazolyl, 1,2,4-triazolyl, pyrazolyl,pyridinyl, pyridazinyl, pyrimidinyl, indolyl, isoindolyl,benzo[b]thiophenyl, benzimidazolyl, benzothiazolyl, pteridinyl, andphenazinyl, where attachment can occur at any point on said rings, aslong as attachment is chemically feasible. Thus, for example,“thiazolyl” refers to thiazol-2-yl, thiazol-4-yl, and thiaz-5-yl.

As used herein, when “heteroaryl” is recited as a possible substituent,the “heteroaryl” group can attach through either a carbon atom or anyheteroatom, to the extent that attachment at that point is chemicallyfeasible.

As used herein, the term “heterocyclylene” refers to an optionallysubstituted bivalent heterocyclyl group (as defined above). The pointsof attachment may be to the same ring atom or to different ring atoms,as long as attachment is chemically feasible. The two points ofattachment can each independently be to either a carbon atom or aheteroatom, as long as attachment is chemically feasible. Examplesinclude, but are not limited to,

where the asterisks indicate ponts of attachment.

As used herein, the term “heteroarylene” refers to an optionallysubstituted bivalent heteroaryl group (as defined above). The points ofattachment may be to the same ring atom or to different ring atoms, aslong as attachment is chemically feasible. The two points of attachmentcan each independently be to either a carbon atom or a heteroatom, aslong as attachment is chemically feasible. Examples include, but are notlimited to,

where the asterisks indicate ponts of attachment.

Various other chemical terms or abbreviations have their standardmeaning to the skilled artisan. For example: “hydroxyl” refers to —OH;“methoxy” refers to —OCH₃; “cyano” refers to —CN; “amino” refers to—NH₂; “methylamino” refers to —NHCH₃; “sulfonyl” refers to —SO₂—;“carbonyl” refers to —C(O)—; “carboxy” or “carboxyl” refer to —CO₂H, andthe like. Further, when a name recited multiple moieties, e.g.,“methylaminocarbonylmethyl”, an earlier-recited moiety is further fromthe point of attachment than any later-recited moieties. Thus, a termsuch as “methylaminocarbonylmethyl” refers to —CH₂—C(O)—NH—CH₃.

As used herein, the term “substituted” refers to substitution of one ormore hydrogens of the designated moiety with the named substituent orsubstituents, multiple degrees of substitution being allowed unlessotherwise stated, provided that the substitution results in a stable orchemically feasible compound. A stable compound or chemically feasiblecompound is one in which the chemical structure is not substantiallyaltered when kept at a temperature from about −80° C. to about +40° C.,in the absence of moisture or other chemically reactive conditions, forat least a week, or a compound which maintains its integrity long enoughto be useful for therapeutic or prophylactic administration to apatient. As used herein, the phrases “substituted with one or more . . .” or “substituted one or more times . . . ” refer to a number ofsubstituents that equals from one to the maximum number of substituentspossible based on the number of available bonding sites, provided thatthe above conditions of stability and chemical feasibility are met.

As used herein, the various functional groups represented will beunderstood to have a point of attachment at the functional group havingthe hyphen or dash (−) or an asterisk (*). In other words, in the caseof —CH₂CH₂CH₃, it will be understood that the point of attachment is theCH₂ group at the far left. If a group is recited without an asterisk ora dash, then the attachment point is indicated by the plain and ordinarymeaning of the recited group.

When any variable occurs more than one time in any one constituent(e.g., R^(d)), or multiple constituents, its definition on eachoccurrence is independent of its definition on every other occurrence.

As used herein, multi-atom bivalent species are to be read from left toright. For example, if the specification or claims recite A-D-E and D isdefined as —OC(O)—, the resulting group with D replaced is: A-OC(O)-Eand not A-C(O)O-E.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur.

As used herein, “administer” or “administering” means to introduce, suchas to introduce to a subject a compound or composition. The term is notlimited to any specific mode of delivery, and can include, for example,intravenous delivery, transdermal delivery, oral delivery, nasaldelivery, and rectal delivery. Furthermore, depending on the mode ofdelivery, the administering can be carried out by various individuals,including, for example, a health-care professional (e.g., physician,nurse, etc.), a pharmacist, or the subject (i.e., self-administration).

As used herein, “treat” or “treating” or “treatment” can refer to one ormore of delaying the progress of a disease or condition, controlling adisease or condition, delaying the onset of a disease or condition,ameliorating one or more symptoms characteristic of a disease orcondition, or delaying the recurrence of a disease or condition orcharacteristic symptoms thereof, depending on the nature of a disease orcondition and its characteristic symptoms.

As used herein, “subject” refers to any mammal such as, but not limitedto, humans. In one embodiment, the subject is a human. In anotherembodiment, the subject is a human who exhibits one or more symptomscharacteristic of a disease or condition. The term “subject” does notrequire one to have any particular status with respect to any hospital,clinic, or research facility (e.g., as an admitted patient, a studyparticipant, or the like).

As used herein, the term “compound” includes free acids, free bases, andany salts thereof. Thus, phrases such as “compound of embodiment 1” or“compound of claim 1” refer to any free acids, free bases, and any saltsthereof that are encompassed by embodiment 1 or claim 1, respectively.

As used herein, the term “pharmaceutical composition” is used to denotea composition that may be administered to a mammalian host, e.g.,orally, topically, parenterally, by inhalation spray, or rectally, inunit dosage formulations containing conventional non-toxic carriers,diluents, adjuvants, vehicles, and the like. The term “parenteral”includes subcutaneous injections

As used herein, “substituted fused imidazole derivatives” refers tocompounds encompassed by Formula (I), described below.

Aspects of the present invention include substituted fused imidazolederivatives, pharmaceutical compositions comprising substituted fusedimidazole derivatives, method of making substituted fused imidazolederivatives, methods of making pharmaceutical compositions comprisingsubstituted fused imidazole derivatives, and methods of use thereof.

In a first aspect, the present invention provides substituted fusedimidazole derivatives that induce production of HMOX1 and thus may beuseful to treat various diseases associated at least in part withoxidative stress.

In a first embodiment (i.e., embodiment 1), the invention provides acompound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein

-   one of X¹, X², X³, and X⁴ is

and the remaining members of X¹, X², X³, and X⁴ are independently N or

-   G is hydrogen, —C₁₋₈ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₆ alkylene-C₃₋₁₀    cycloaklyl, heterocyclyl, —C₁₋₆ alkylene-C₃₋₁₀ heterocyclyl, phenyl,    heteroaryl, or NR^(h)R^(k), where the alkyl, alkylene, cycloalkyl,    heterocyclyl, phenyl, and heteroaryl groups are optionally    substituted one or more times with substituents independently    selected from R^(c); or G is —CH₂Y³, —CH₂CH₂Y³, —CH₂CH₂CH₂Y³,    —CH(CH₃)CH₂Y³, —CH₂CH(Y³)CH₃, —CH(Y³)CH₃, —CH₂C(Y³)(CH₃)₂,    —C(Y³)(CH₃)₂, or

where Y³ is cyclopropyl, —CF₃, —OCF₃, —OCH₃, —OCH₂CH₃, —F, —Cl, —OH,—O(CH₂)₂—OH, —O(CH₂)₂—F, —SCH₃, —S(O)₂—CH₃, —SCH₂CH₃, —S(O)₂CH₂CH₃,—NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂, tetrahydropyran-4-yl,tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl,4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH₃,—NH—C(O)—CH₂CH₃, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y⁴, where Y⁴is —OH, —OCH₃, —OCH₂CH₃, —OC(CH₃)₃, —NH₂, —NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl,or piperazin-1-yl;

-   L is —CH₂—C(O)N(R⁶)—, —C(O)N(R⁶)—, —C(O)—O—, —SO₂—, —C(O)—,    heteroarylene optionally substituted one or more times with    substituents independently selected from R^(x), or heterocyclylene    optionally substituted one or more times with substituents    independently selected from R^(x); or the group -L-G is -cyano;-   R¹ is hydrogen, R^(a), phenyl, or heteroaryl, where the phenyl and    heteroaryl groups are optionally substituted one or more times with    substituents independently selected from R^(x);-   R² is R^(b);-   R³ is hydrogen, —C₁₋₆ alkyl, or —C₁₋₆ alkylene-C₃₋₁₀ cycloaklyl,    where the alkyl, alkylene, and cycloalkyl groups are optionally    substituted one or more times with substituents independently    selected from R^(z);-   R⁴ is —C₁₋₆ alkyl or —C₁₋₆ alkylene-C₃₋₁₀ cycloaklyl, where the    alkyl, alkylene, and cycloalkyl groups are optionally substituted    one or more times with substituents independently selected from    R^(y);-   R⁶ is hydrogen, —C₁₋₆ alkyl, —C₁₋₆ alkylene-C₃₋₁₀ cycloaklyl, where    the alkyl, alkylene, and cycloalkyl groups are optionally    substituted one or more times with substituents independently    selected from R^(x);-   R^(a) is    -   a) -halogen,    -   b) —C₁₋₆ alkyl,    -   c) —C₃₋₁₀ cycloalkyl,    -   d) -heterocyclyl,    -   e) -cyano,    -   f) —CF₃,    -   g) —OCF₃,    -   h) —O—R^(d),    -   i) —S(O)_(w-)R^(d),    -   j) —S(O)₂₀—R^(d),    -   k) —NR^(d)R^(e),    -   l) —C(O)—R^(d),    -   m) —C(O)—O—R^(d),    -   n) —OC(O)—R^(d),    -   o) —C(O)NR^(d)R^(e),    -   p) —C(O)-heterocyclyl,    -   q) —NR^(d)C(O)R^(e),    -   r) —OC(O)NR^(d)R^(e),    -   s) —NR^(d)C(O)OR^(d), or    -   t) —NR^(d)C(O)NR^(d)R^(e),    -   where the alkyl, cycloalkyl, and heterocyclyl groups are        optionally substituted one or more times with substituents        independently selected from R^(y);-   R^(b) is    -   a) -halogen,    -   b) —C₁₋₆ alkyl,    -   c) —C₃₋₁₀ cycloalkyl,    -   d) -heterocyclyl,    -   e) -phenyl,    -   f) -heteroaryl,    -   g) -cyano,    -   h) —CF₃,    -   i) —OCF₃,    -   j) —O—R^(f),    -   k) —S(O)_(w)—R^(f),    -   l) —S(O)₂O—R^(f),    -   m) —NR^(f)R^(g),    -   n) —C(O)—R^(f),    -   o) —C(O)—O—R^(f),    -   p) —OC(O)—R^(f),    -   q) —C(O)NR^(f)R^(g),    -   r) —C(O)-heterocyclyl,    -   s) —NR^(f)C(O)R^(g),    -   t) —OC(O)NR^(f)R^(g),    -   u) —NR C(O)OR^(f), or    -   v) —NR C(O)NR^(f)R^(g),    -   where the alkyl, cycloalkyl, heterocyclyl, phenyl, and        heteroaryl groups are optionally substituted one or more times        with substituents independently selected from R^(z);-   R^(c) is    -   a) -halogen,    -   b) —C₁₋₆ alkyl,    -   c) —C₃₋₁₀ cycloalkyl,    -   d) -heterocyclyl,    -   e) -cyano,    -   f) —CF₃,    -   g) —OCF₃,    -   h) —O—R^(h),    -   i) —S(O)_(w)—R^(h),    -   j) —S(O)₂O—R^(h),    -   k) —NR^(h)R^(k),    -   l) —C(O)—R^(h),    -   m) —C(O)—O—R^(h),    -   n) —OC(O)—R^(h),    -   o) —C(O)NR^(h)R^(k),    -   p) —C(O)-heterocyclyl,    -   q) —NR^(h)C(O)R^(k),    -   r) —OC(O)NR^(h)R^(k),    -   s) —NR^(h)C(O)OR^(k),    -   t) —NR^(h)C(O)NR^(h)R^(k),    -   u) —NR^(h)S(O)_(w)R^(k),    -   v) -phenyl,    -   w) -heteroaryl, or    -   x) —O—(C₁₋₄ alkylene)-O—(C₁₋₄ alkylene)-N(R^(h))C(O)—OR^(k),    -   where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and        heteroaryl groups are optionally substituted one or more times        with substituents independently selected from R^(x);-   R^(d) and R^(e) are independently hydrogen, C₁₋₆ alkyl, or C₃₋₁₀    cycloalkyl, where the alkyl and cycloalkyl groups are optionally    substituted one or more times with substituents independently    selected from R^(y); or, if R^(d) and R^(e) are both attached to the    same nitrogen atom, together with that nitrogen atom may optionally    form a heterocyclic ring selected from the group consisting of    azetidino, pyrrolidino, pyrazolidino, imidazolidino, oxazolidino,    isoxazolidino, thiazolidino, isothiazolidino, piperidino,    piperazino, morpholino, thiomorpholino, and azepano, where each ring    is optionally substituted one or more times with substituents    independently selected from R^(y);-   R^(f) and R^(g) are independently hydrogen, C₁₋₆ alkyl, C₃₋₁₀    cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl,    phenyl, and heteroaryl groups are optionally substituted one or more    times with substituents independently selected from R^(z); or, if    R^(f) and R^(g) are both attached to the same nitrogen atom,    together with that nitrogen atom may optionally form a heterocyclic    ring selected from the group consisting of azetidino, pyrrolidino,    pyrazolidino, imidazolidino, oxazolidino, isoxazolidino,    thiazolidino, isothiazolidino, piperidino, piperazino, morpholino,    thiomorpholino, and azepano, where each ring is optionally    substituted one or more times with substituents independently    selected from R^(z);-   R^(h) and R^(k) are independently hydrogen, C₁₋₆ alkyl, C₃₋₁₀    cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where the alkyl,    cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups are    optionally substituted one or more times with substituents    independently selected from R^(x); or, if R^(h) and R^(k) are both    attached to the same nitrogen atom, together with that nitrogen atom    may optionally form a heterocyclic ring selected from the group    consisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino,    oxazolidino, isoxazolidino, thiazolidino, isothiazolidino,    piperidino, piperazino, morpholino, thiomorpholino, and azepano,    where each ring is optionally substituted one or more times with    substituents independently selected from R^(x);-   R^(y) is    -   a) -halogen,    -   b) —NH₂,    -   c) -cyano,    -   d) -carboxy,    -   e) -hydroxy,    -   f) -thiol,    -   g) —CF₃,    -   h) —OCF₃,    -   i) —C(O)—NH₂,    -   j) —S(O)₂—NH₂,    -   k) oxo,    -   l) —C₁₋₆ alkyl, optionally substituted one or more times with        substitutents selected independently from the group consisting        of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and        —N(C₁₋₆ alkyl)₂,    -   m) -heterocyclyl optionally substituted one or more times with        one or more times with substitutents selected independently from        the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   n) —C₃₋₁₀ cycloalkyl optionally substituted one or more times        with one or more times with substitutents selected independently        from the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   o) —O—C₁₋₆ alkyl optionally substituted one or more times with        one or more times with substitutents selected independently from        the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   p) —O—C₃₋₁₀ cycloalkyl optionally substituted one or more times        with one or more times with substitutents selected independently        from the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   q) —NH—C₁₋₆ alkyl optionally substituted one or more times with        one or more times with substitutents selected independently from        the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   r) —N(C₁₋₆ alkyl)₂ optionally substituted one or more times with        one or more times with substitutents selected independently from        the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   s) —C(O)—C₁₋₆ alkyl, optionally substituted one or more times        with one or more times with substitutents selected independently        from the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   t) —C(O)—O—C₁₋₆ alkyl, optionally substituted one or more times        one or more times with substitutents selected independently from        the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   u) —S—C₁₋₆ alkyl, optionally substituted one or more times with        one or more times with substitutents selected independently from        the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   v) —S(O)₂—C₁₋₆ alkyl, optionally substituted one or more times        one or more times with substitutents selected independently from        the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   w) —C(O)—NH—C₁₋₆ alkyl, optionally substituted one or more times        one or more times with substitutents selected independently from        the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   x) —C(O)—N(C₁₋₆ alkyl)₂, optionally substituted one or more        times one or more times with substitutents selected        independently from the group consisting of halogen, —OH, —O—C₁₋₆        alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   y) —S(O)₂—NH—C₁₋₆ alkyl, optionally substituted one or more        times one or more times with substitutents selected        independently from the group consisting of halogen, —OH, —O—C₁₋₆        alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   z) —S(O)₂—N(C₁₋₆ alkyl)₂, optionally substituted one or more        times one or more times with substitutents selected        independently from the group consisting of halogen, —OH, —O—C₁₋₆        alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   aa) —NH—C(O)—C₁₋₆ alkyl, optionally substituted one or more        times one or more times with substitutents selected        independently from the group consisting of halogen, —OH, —O—C₁₋₆        alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂, or    -   bb) —NH—S(O)₂—C₁₋₆ alkyl, optionally substituted one or more        times one or more times with substitutents selected        independently from the group consisting of halogen, —OH, —O—C₁₋₆        alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂;-   R^(x) is    -   a) —R^(y)    -   b) -phenyl, optionally substituted one or more times with one or        more times with substitutents selected independently from the        group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆        alkyl, and —N(C₁₋₆ alkyl)₂,    -   c) -heteroaryl, optionally substituted one or more times with        one or more times with substitutents selected independently from        the group consisting of halogen, —OH, —O—C₁₋₆ alkyl, —NH₂,        —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,    -   d) —O-phenyl,    -   e) —O-heteroaryl,    -   f) —C(O)-phenyl,    -   g) —C(O)-heteroaryl,    -   h) —C(O)—O-phenyl, or    -   i) —C(O)—O-heteroaryl;-   R^(z) is    -   a) —R^(y)    -   b) -phenyl,    -   c) -heteroaryl;    -   d) —O-phenyl,    -   e) —O-heteroaryl,    -   f) —C(O)-phenyl,    -   g) —C(O)-heteroaryl,    -   h) —C(O)—O-phenyl, or    -   i) —C(O)—O-heteroaryl;-   v is an integer from 0 to 4, and-   w is an integer from 0 to 2.

Embodiment 2

A compound according to embodiment 1 wherein

-   G is hydrogen, —C₁₋₈ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₆ alkylene-C₃₋₁₀    cycloaklyl, heterocyclyl, phenyl, heteroaryl, or NR^(h)R^(k), where    the alkyl, alkylene, cycloalkyl, heterocyclyl, phenyl, and    heteroaryl groups are optionally substituted one or more times with    substituents independently selected from R^(c); or G is —CH₂Y³,    —CH₂CH₂Y³, —CH₂CH₂CH₂Y³, —CH(CH₃)CH₂Y³, —CH₂CH(Y³)CH₃, —CH(Y³)CH₃,    —CH₂C(Y³)(CH₃)₂, —C(Y³)(CH₃)₂, or

where Y³ is -cyclopropyl, —CF₃, —OCF₃, —OCH₃, —OCH₂CH₃, —F, —Cl, —OH,—O(CH₂)₂—OH, —O(CH₂)₂—F, —SCH₃, —S(O)₂—CH₃, —SCH₂CH₃, —S(O)₂CH₂CH₃,—NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂, tetrahydropyran-4-yl,tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl,4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH₃,—NH—C(O)—CH₂CH₃, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y⁴, where Y⁴is —OH, —OCH₃, —OCH₂CH₃, —OC(CH₃)₃, —NH₂, —NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl,or piperazin-1-yl;

-   R^(c) is    -   a) -halogen,    -   b) —C₁₋₆ alkyl,    -   c) —C₃₋₁₀ cycloalkyl,    -   d) -heterocyclyl,    -   e) -cyano,    -   f) —CF₃,    -   g) —OCF₃,    -   h) —O—R^(h),    -   i) —S(O)_(w)—R^(h),    -   j) —S(O)₂O—R^(h),    -   k) —NR^(h)R^(k),    -   l) —C(O)—R^(h),    -   m) —C(O)—O—R^(h),    -   n) —OC(O)—R^(h),    -   o) —C(O)NR^(h)R^(k),    -   p) —C(O)-heterocyclyl,    -   q) —NR^(h)C(O)R^(k),    -   r) —OC(O)NR^(h)R^(k),    -   s) —NR^(h)C(O)OR^(k),    -   t) —NR^(h)C(O)NR^(h)R^(k),    -   u) -phenyl,    -   v) -heteroaryl, or    -   w) —O—(C₁₋₄ alkylene)-O—(C₁₋₄ alkylene)-N(R^(h))C(O)—OR^(k),    -   where the alkylene, alkyl, cycloalkyl, heterocyclyl, phenyl, and        heteroaryl groups are optionally substituted one or more times        with substituents independently selected from R^(x);-   R^(h) and R^(k) are independently hydrogen, C₁₋₆ alkyl, C₃₋₁₀    cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl,    phenyl, and heteroaryl groups are optionally substituted one or more    times with substituents independently selected from R^(x); or, if    R^(h) and R^(k) are both attached to the same nitrogen atom,    together with that nitrogen atom may optionally form a heterocyclic    ring selected from the group consisting of azetidino, pyrrolidino,    pyrazolidino, imidazolidino, oxazolidino, isoxazolidino,    thiazolidino, isothiazolidino, piperidino, piperazino, morpholino,    thiomorpholino, and azepano, where each ring is optionally    substituted one or more times with substituents independently    selected from R^(x); and-   R^(y) is    -   a) -halogen,    -   b) —NH₂,    -   c) -cyano,    -   d) -carboxy,    -   e) —C₁₋₆ alkyl, optionally substituted one or more times with        halogen,    -   f) -heterocyclyl, optionally substituted one or more times with        halogen,    -   g) —C₃₋₁₀ cycloalkyl, optionally substituted one or more times        with halogen,    -   h) —O—C₁₋₆ alkyl, optionally substituted one or more times with        halogen,    -   i) —O—C₃₋₁₀ cycloalkyl, optionally substituted one or more times        with halogen,    -   j) -hydroxy,    -   k) -thiol,    -   l) —CF₃,    -   m) —OCF₃,    -   n) —C(O)—C₁₋₆ alkyl, optionally substituted one or more times        with halogen,    -   o) —C(O)—O—C₁₋₆ alkyl, optionally substituted one or more times        with halogen,    -   p) —S—C₁₋₆ alkyl, optionally substituted one or more times with        halogen, or    -   q) —S(O)₂—C₁₋₆ alkyl, optionally substituted one or more times        with halogen.

Embodiment 3

A compound according to embodiment 2, wherein

-   -   R³ is hydrogen.

Embodiment 4

A compound according to embodiment 2, wherein

-   -   R³ is methyl.

Embodiment 5

A compound according to embodiment 2, wherein

-   -   R³ is ethyl.

Embodiment 6

A compound according to embodiment 2, wherein

-   -   R³ is isopropyl.

Embodiment 7

A compound according to any one of embodiments 2 to 6, wherein

-   -   X³ is

and X¹, X², and X⁴ are

Embodiment 8

A compound according to any one of embodiments 2 to 6, wherein

-   -   X³ is

and X¹ and X⁴ are

and X² is N. Embodiment 9

A compound according to any one of embodiments 2 to 6, wherein

-   -   X³ is

and X¹ and X² are

and X⁴ is N. Embodiment 10

A compound according to any one of embodiments 2 to 6, wherein

-   -   X³ is

and X² and X⁴ are

and X¹ is N. Embodiment 11

A compound according to any one of embodiments 2 to 6, wherein

-   -   X² is

and X¹, X³, and X⁴ are

Embodiment 12

A compound according to any one of embodiments 2 to 6, wherein

-   -   X² is

and X¹ and X⁴ are

and X³ is N. Embodiment 13

A compound according to any one of embodiments 2 to 6, wherein

-   -   X² is

and X¹ and X³ are

and X⁴ is N. Embodiment 14

A compound according to any one of embodiments 2 to 6, wherein

-   -   X² is

and X³ and X⁴ are

and X¹ is N. Embodiment 15

A compound according to any one of embodiments 2 to 6, wherein

-   -   X² is

and two of X¹, X³, and X⁴ are N.

Embodiment 16

A compound according to any one of embodiments 2 to 6, wherein

-   -   X³ is

and two of X¹, X², and X⁴ are N.

Embodiment 17

A compound according to any one of embodiments 2 to 6, wherein

-   -   X² is

and X¹, X³, and X⁴ are N.

Embodiment 18

A compound according to any one of embodiments 2 to 6, wherein

-   -   X³ is

and X¹, X², and X⁴ are N.

Embodiment 19

A compound according to any one of embodiments 2 to 18, wherein

-   -   v is an integer from 0 to 2.

Embodiment 20

A compound according to any one of embodiments 2 to 18, wherein

-   -   v is 0 or 1.

Embodiment 21

A compound according to any one of embodiments 2 to 18, wherein

-   -   v is 1.

Embodiment 22

A compound according to any one of embodiments 2 to 18, wherein

-   -   v is 1, and R² is attached at either the 5-position or the        6-position of the benzothiazole ring.

Embodiment 23

A compound according to any one of embodiments 2 to 18, wherein

-   -   v is 1, and R² is attached at the 6-position of the        benzothiazole ring.

Embodiment 24

A compound according to any one of embodiments 2 to 18, wherein

-   -   v is 2, and one R² is attached at the 6-position of the        benzothiazole ring.

Embodiment 25

A compound according to any one of embodiments 2 to 18, wherein

-   -   v is 2, and R² is attached at the 5-position and the 6-position        of the benzothiazole ring.

Embodiment 26

A compound according to any one of embodiments 2 to 25, wherein

-   -   R² is -halogen, —C₁₋₆ alkyl, —CF₃, —OCF₃, —O—R^(f), or        —S(O)_(w)—R^(f), where the alkyl group is optionally substituted        one or more times with substituents independently selected from        R^(z).

Embodiment 27

A compound according to any one of embodiments 2 to 25, wherein

-   -   R² is -halogen, -methyl, —CF₃, —OCF₃, —SCF₃, —O-heteroaryl, or        —S(O)₂—CH₃.

Embodiment 28

A compound according to any one of embodiments 2 to 25, wherein

-   -   R² is selected from —Cl, —F, —CF₃, and —OCF₃.

Embodiment 29

A compound according to any one of embodiments 2 to 25, wherein

-   -   R² is —OCF₃.

Embodiment 30

A compound according to any one of embodiments 2 to 25, wherein

-   -   R² is —CF₃.

Embodiment 31

A compound according to any one of embodiments 2 to 25, wherein

-   -   R² is —F.

Embodiment 32

A compound according to any one of embodiments 2 to 25, wherein

-   -   R² is —Cl.

Embodiment 33

A compound according to any one of embodiments 2 to 32, wherein

-   -   R⁴ is -methyl, -ethyl, -n-propyl, -isopropyl, -n-butyl,        -sec-butyl, -isobutyl, -tert-butyl, —(CH₂)₁₋₂—OCH₃, —(CH₂)₁₋₂—F,        —(CH₂)₁₋₂—Cl, —(CH₂)₁₋₂—OCF₃, —(CH₂)₁₋₂—NH₂, —(CH₂)₁₋₂—CN,        —(CH₂)₁₋₂—OH, —(CH₂)₁₋₂—CF₃, —(CH₂)₁₋₂—CO₂H, —(CH₂)₁₋₂—SH,        —(CH₂)₁₋₂—SCH₃, —(CH₂)₁₋₂—S(O)₂CH₃, —(CH₂)₁₋₂—OCH₂CH₃,        —(CH₂)₁₋₂—SCH₂CH₃, —(CH₂)₁₋₂—S(O)₂CH₂CH₃, —(CH₂)₁₋₂—NH—CH₃, or        —(CH₂)₁₋₂—N(CH₃)₂.

Embodiment 34

A compound according to any one of embodiments 2 to 33, wherein

-   -   R⁴ is -methyl, -ethyl, -isopropyl, -isobutyl, —CH₂CH₂—OCH₃,        —CH₂CH₂—F, or —CH₂CH₂—NH₂.

Embodiment 35

A compound according to any one of embodiments 2 to 34, wherein

-   -   R⁴ is -methyl, -ethyl, -isopropyl, or -isobutyl.

Embodiment 36

A compound according to any one of embodiments 2 to 35, wherein

-   -   R⁴ is -methyl.

Embodiment 37

A compound according to any one of embodiments 2 to 35, wherein

-   -   R⁴ is -ethyl.

Embodiment 38

A compound according to any one of embodiments 2 to 33, wherein

-   -   R⁴ is —(CH₂)₂—OCH₃, —(CH₂)₂—F, —(CH₂)₂—Cl, —(CH₂)₂—OCF₃,        —(CH₂)₂—NH₂, —(CH₂)₂—CN, —(CH₂)₂—OH, —(CH₂)₂—CF₃, —(CH₂)₂—CO₂H,        —(CH₂)₂—SH, —(CH₂)₂—SCH₃, or —(CH₂)₂—S(O)₂CH₃.

Embodiment 39

A compound according to any one of embodiments 2 to 38, wherein

-   -   R¹ is independently selected from hydrogen, —OCH₃, —F, —Cl,        —NH₂, -cyano, —OH, —CF₃, —OCF₃, —SH, —S—C₁₋₆ alkyl, —S(O)₂—C₁₋₆        alkyl, —CO₂H, —NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, and —NH—C₁₋₆        alkyl.

Embodiment 40

A compound according to any one of embodiments 2 to 38, wherein

-   -   R¹ is independently selected from —OCH₃, —F, —CF₃, —OCF₃,        —N(CH₃)₂, —N(CH₂CH₃)₂, and —N(CH₃)(CH₂CH₃).

Embodiment 41

A compound according to any one of embodiments 2 to 38, wherein

-   -   R¹ is independently selected from hydrogen, —OCH₃, and —F.

Embodiment 42

A compound according to any one of embodiments 2 to 38, wherein

-   -   R¹ is hydrogen.

Embodiment 43

A compound according to any one of embodiments 2 to 41, wherein

-   -   no more than one R¹ substituent is not hydrogen.

Embodiment 44

A compound according to any one of embodiments 2 to 43, wherein

-   -   G is hydrogen, —C₁₋₈ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₆        alkylene-C₃₋₈ cycloaklyl, heterocyclyl, or NR^(h)R^(k), where        the alkyl, alkylene, cycloalkyl, and heterocyclyl groups are        optionally substituted one or more times with substituents        independently selected from R^(c); or G is —CH₂Y³, —CH₂CH₂Y³,        —CH₂CH₂CH₂Y³, —CH(CH₃)CH₂Y³, —CH₂CH(Y³)CH₃, —CH(Y³)CH₃,        —CH₂C(Y³)(CH₃)₂, —C(Y³)(CH₃)₂, or

where Y³ is -cyclopropyl, —CF₃, —OCF₃, —OCH₃, —OCH₂CH₃, —F, —Cl, —OH,—O(CH₂)₂—OH, —O(CH₂)₂—F, —SCH₃, —S(O)₂—CH₃, —SCH₂CH₃, —S(O)₂CH₂CH₃,—NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂, tetrahydropyran-4-yl,tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl,4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH₃,—NH—C(O)—CH₂CH₃, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y⁴, where Y⁴is —OH, —OCH₃, —OCH₂CH₃, —OC(CH₃)₃, —NH₂, —NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl,or piperazin-1-yl;

-   -   L is —CH₂—C(O)N(R⁶)—, —C(O)N(R⁶)—, —C(O)—O—, —SO₂—, —C(O)—, or        heterocyclylene optionally substituted one or more times with        substituents independently selected from R^(x); or the group        -L-G is -cyano;    -   R¹ is hydrogen or R^(a);    -   R^(c) is        -   a) -halogen,        -   b) —C₁₋₆ alkyl,        -   c) —C₃₋₁₀ cycloalkyl,        -   d) -heterocyclyl,        -   e) -cyano,        -   f) —CF₃,        -   g) —OCF₃,        -   h) —O—R^(h),        -   i) —S(O)_(w)—R^(h),        -   j) —S(O)₂O—R^(h),        -   k) —NR^(h)R^(k),        -   l) —C(O)—R^(h),        -   m) —C(O)—O—R^(h),        -   n) —OC(O)—R^(h),        -   o) —C(O)NR^(h)R^(k),        -   p) —C(O)-heterocyclyl,        -   q) —NR^(h)C(O)R^(k),        -   r) —OC(O)NR^(h)R^(k),        -   s) —NR^(h)C(O)OR^(k),        -   t) —NR^(h)C(O)NR^(h)R^(k), or        -   u) —O—(C₁₋₄ alkylene)-O—(C₁₋₄ alkylene)-N(R^(h))C(O)—OR^(k),        -   where the alkylene, alkyl, cycloalkyl, and heterocyclyl            groups are optionally substituted one or more times with            substituents independently selected from R^(x);    -   R^(h) and R^(k) are independently hydrogen, C₁₋₆ alkyl, or C₃₋₁₀        cycloalkyl, where the alkyl, and cycloalkyl groups are        optionally substituted one or more times with substituents        independently selected from R^(x); or, if R^(h) and R^(k) are        both attached to the same nitrogen atom, together with that        nitrogen atom may optionally form a heterocyclic ring selected        from the group consisting of azetidino, pyrrolidino,        pyrazolidino, imidazolidino, oxazolidino, isoxazolidino,        thiazolidino, isothiazolidino, piperidino, piperazino,        morpholino, thiomorpholino, and azepano, where each ring is        optionally substituted one or more times with substituents        independently selected from R^(x); and    -   R^(x) is R^(y).

Embodiment 45

A compound according to any one of embodiments 2 to 44, wherein

-   -   L-G is not -cyano.

Embodiment 46

A compound according to any one of embodiments 2 to 45, wherein

-   -   L-G is —C(O)NR^(h)R^(k).

Embodiment 47

A compound according to any one of embodiments 2 to 45, wherein

-   -   L is —C(O)N(R⁶)— or —C(O)—O—.

Embodiment 48

A compound according to any one of embodiments 2 to 45, wherein

-   -   L is —C(O)N(R⁶)—.

Embodiment 49

A compound according to any one of embodiments 2 to 45, wherein

-   -   L is not —CH₂—C(O)N(R⁶)—.

Embodiment 50

A compound according to any one of embodiments 2 to 45, wherein

-   -   L is —C(O)—O—.

Embodiment 51

A compound according to any one of embodiments 2 to 45, wherein

-   -   L is —C(O)—.

Embodiment 52

A compound according to any one of embodiments 2 to 45, wherein

-   -   L is —S(O)₂—.

Embodiment 53

A compound according to any one of embodiments 2 to 43, wherein

-   -   L is heteroarylene optionally substituted one or more times with        substituents independently selected from R^(x).

Embodiment 54

A compound according to any one of embodiments 2 to 53, wherein

-   -   R⁶ is hydrogen.

Embodiment 55

A compound according to any one of embodiments 2 to 53, wherein

-   -   R⁶ is hydrogen or -methyl.

Embodiment 56

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is hydrogen, —C₁₋₈ alkyl, —C₃₋₁₀ cycloalkyl, or —C₁₋₆        alkylene-C₃₋₈ cycloaklyl, where the alkyl, cycloalkyl, and        alkylene groups are optionally substituted one or more times        with substituents independently selected from R^(x).

Embodiment 57

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is —H, -methyl, -ethyl, -n-propyl, -isopropyl, -isobutyl,        —CH₂Y³, —CH₂CH₂Y³, —CH₂CH₂CH₂Y³, —CH(CH₃)CH₂Y³, —CH₂CH(Y³)CH₃,        —CH(Y³)CH₃, —CH₂C(Y³)(CH₃)₂, or —C(Y³)(CH₃)₂, where Y³ is        -cyclopropyl, —CF₃, —OCF₃, —OCH₃, —OCH₂CH₃, —F, —OH,        —O(CH₂)₂—OH, —O(CH₂)₂—F, —SCH₃, —S(O)₂—CH₃, —SCH₂CH₃,        —S(O)₂CH₂CH₃, —NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂, —NH—C(O)—CH₃,        —NH—C(O)—CH₂CH₃, or C(O)—Y⁴, where Y⁴ is —OH, —OCH₃, —OCH₂CH₃,        —OC(CH₃)₃, —NH₂, —NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂, or —N(CH₂CH₃)₂.

Embodiment 58

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is -methyl, -ethyl, -n-propyl, -isopropyl, or -isobutyl, where        each is optionally substituted one or more times with        substituents independently selected from —CF₃, —OCF₃, —OCH₃,        —OCH₂CH₃, —F, —OH, —O(CH₂)₂—OH, —O(CH₂)₂—F, —SCH₃, —SCH₂CH₃,        —NH—CH₃, —NH—CH₂CH₃, and —N(CH₃)₂.

Embodiment 59

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is H.

Embodiment 60

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is C₁₋₈ alkyl optionally substituted one or more times with        halogen.

Embodiment 61

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is C₃₋₁₀ cycloalkyl optionally substituted one or more times        with halogen.

Embodiment 62

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is heterocyclyl optionally substituted one or more times with        halogen.

Embodiment 63

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is —C₁₋₆ alkylene-C₃₋₁₀ cycloalkyl optionally substituted one        or more times with halogen.

Embodiment 64

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is NR^(h)R^(k).

Embodiment 65

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is —CH₂—R^(c).

Embodiment 66

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is —CH₂CH₂—R^(c).

Embodiment 67

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is —CH₂CH₂CH₂—R^(c).

Embodiment 68

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is —CH(CH₃)CH₂R^(c).

Embodiment 69

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is —CH₂CH(R^(c))CH₃.

Embodiment 70

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is —CH(R^(c))CH₃.

Embodiment 71

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is —CH₂C(R^(c))(CH₃)₂.

Embodiment 72

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is —C(R^(c))(CH₃)₂.

Embodiment 73

A compound according to any one of embodiments 2 to 55, wherein

-   -   G is imidazol-2-yl, thiazol-2yl, oxazol-2-yl, pyrazol1-yl,        furan-2yl, thiophen-2-yl, pyrrol-1-yl, 1H-1,2,4-triazolyl-3-yl,        5-methyl-1H-1,2,4-triazolyl-3-yl, —(CH₂)₁₋₃-(imidazol-2-yl),        —(CH₂)₁₋₃-(thiazol-2yl), —(CH₂)₁₋₃-(oxazol-2-yl),        —(CH₂)₁₋₃-(pyrazol1-yl), —(CH₂)₁₋₃-(furan-2yl),        —(CH₂)₁₋₃-(thiophen-2-yl), —(CH₂)₁₋₃-(pyrrol-1-yl),        —(CH₂)₁₋₃-(1H-1,2,4-triazolyl-3-yl), or        —(CH₂)₁₋₃-(5-methyl-1H-1,2,4-triazolyl-3-yl).

Embodiment 74

A compound according to any one of embodiments 2 to 73, wherein

-   -   the compound is in its free (non-salted) form.

Embodiment 75

A compound according to any one of embodiments 2 to 73, wherein

-   -   the compound is in the form of a pharmaceutically acceptable        salt.

Embodiment 76

A compound according to any one of embodiments 1 to 75, wherein

-   -   any “heterocyclyl” group present in the compound is selected        from the group consisting of: azetidin-1-yl, azetidin-2-yl,        azetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,        pyrrolidin-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,        tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl,        pyrazolidin-1-yl, pyrazolidin-3-yl, pyrazolidin-4-yl,        imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl,        oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl,        oxazolidin-5-yl, isoxazolidin-2-yl, isoxazolidin-3-yl,        isoxazolidin-4-yl, isoxazolidin-5-yl, thiazolidin-2-yl,        thiazolidin-3-yl, thiazolidin-4-yl, thiazolodin-5-yl,        isothiazolidin-2-yl, isothiazolidin-3-yl, isothiazolidin-4-yl,        isothiazolodin-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,        1,3-oxathiolan-2-yl, 1,3-oxathiolane-4-yl, 1,3-oxathiolan-5-yl,        1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, 1,3-dithiolan-2-yl,        1,3-dithiolan-4-yl, piperidin-1-yl, piperidin-2-yl,        piperidin-3-yl, piperidin-4-yl, tetrahydropyran-2-yl,        tetrahydropyran-3-yl, tetrahydropyran-4-yl, thian-2-yl,        thian-3-yl, thian-4-yl, piperazin-1-yl, piperazin-2-yl,        morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,        thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl,        1,4-dioxan-2-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl,        1,3-dioxan-5-yl, 1,4-dithian-2-yl, 1,3-dithian-2-yl,        1,3-dithian-4-yl, 1,3-dithian-5-yl, 1,2-dithian-3-yl,        1,2-dithian-4-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl, and        azepan-4-yl, where each of these named rings may optionally be        substituted one or more times with substituents independently        selected from halogen, —NH₂, cyano, carboxy, C₁₋₄ alkyl, C₃₋₁₀        cycloalkyl, hydroxyl, thiol, —CF₃, —OCF₃, —O—C₁₋₄ alkyl,        —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —S—C₁₋₄ alkyl, —S(O)₂—C₁₋₄        alkyl, —C(O)—C₁₋₄ alkyl, —C(O)O—C₁₋₄ alkyl, —C(O)NH₂,        —C(O)NH—C₁₋₄ alkyl, and —C(O)N(C₁₋₄ alkyl)₂, and where any        nitrogen atom in any of these named rings may optionally be        oxidized when chemically feasible, and where any sulfur atom in        any of these named rings may optionally be oxidized once or        twice when chemically feasible.

Embodiment 77

A compound according to any one of embodiments 1 to 76, wherein any“heteroaryl” group present in the compound is selected from the groupconsisting of: 1H-pyrrol-1-yl, 1H-pyrrol-2-yl, 1H-pyrrol-3-yl,furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 1H-imidazol-1-yl,1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1H-pyrazol-1-yl,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, oxazol-2-yl,oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, isothiazol-3-yl,isothiazol-4-yl, isothiazol-5-yl, 1H-1,2,3-triazol-1-yl,1H-1,2,3-triazol-4-yl, 1H-1,2,3-triazol-5-yl, 1H-1,2,4-triazol-1-yl,1H-1,2,4-triazol-3-yl, 1H-1,2,4-triazol-5-yl, furazan-3-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl,pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,pyrazin-2-yl, 1,3,5-triazin-2-yl, 1H-indol-1-yl, 1H-indol-2-yl,1H-indol-3-yl, 2H-isoindol-1-yl, 2H-isoindol-2-yl, quinolin-2-yl,quinolin-3-yl, quinolin-4-yl, isoquinolin-1-yl, isoquinolin-3-yl,isoquinolin-4-yl, benzoxazol-2-yl, benzothiazol-2-yl,1H-benzimidazol-1-yl, 1H-benzimidazol-2-yl, benzofuran-2-yl,benzofuran-3-yl, benzothiophen-2-yl, and benzothiophen-3-yl, where eachof these named rings may optionally be substituted one or more timeswith substituents independently selected from halogen, —NH₂, cyano,carboxy, C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl, hydroxyl, thiol, —CF₃, —OCF₃,—O—C₁₋₄ alkyl, —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —S—C₁₋₄ alkyl,—S(O)₂—C₁₋₄ alkyl, —C(O)—C₁₋₄ alkyl, —C(O)O—C₁₋₄ alkyl, —C(O)NH₂,—C(O)NH—C₁₋₄ alkyl, —C(O)N(C₁₋₄ alkyl)₂, and phenyl.

Embodiment 78

A compound according to any one of embodiments 1 to 77, wherein any“heteroarylene” group present in the compound is selected from the groupconsisting of: 1H-pyrrol-2,5-diyl, furan-2,5-diyl, thiophen-2,5-diyl,1H-imidazol-2,4-diyl, 1H-imidazol-2,5-diyl, oxazol-2,4-diyl,oxazol-2,5-diyl, thiazol-2,4-diyl, thiazol-2,5-diyl,1H-1,2,4-triazol-3,5-diyl, and 2H-isoindol-1,3-diyl, where each of thesenamed rings may optionally be substituted one or more times withsubstituents independently selected from halogen, —NH₂, cyano, carboxy,—C₁₋₄alkyl, —C₃₋₁₀ cycloalkyl, hydroxyl, thiol, —CF₃, —OCF₃, —O—C₁₋₄alkyl, —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —S—C₁₋₄ alkyl, —S(O)₂—C₁₋₄alkyl, —C(O)—C₁₋₄ alkyl, —C(O)O—C₁₋₄ alkyl, —C(O)NH₂, —C(O)NH—C₁₋₄alkyl, —C(O)N(C₁₋₄ alkyl)₂, and phenyl.

Embodiment 79

A compound according to embodiment 1.

Embodiment 80

A compound according to embodiment 79, wherein

-   -   R³ is hydrogen.

Embodiment 81

A compound according to embodiment 79, wherein

-   -   R³ is methyl.

Embodiment 82

A compound according to embodiment 79, wherein

-   -   R³ is ethyl.

Embodiment 83

A compound according to embodiment 79, wherein

-   -   R³ is isopropyl.

Embodiment 84

A compound according to any one of embodiments 79 to 83, wherein

-   -   X³ is

and X¹, X², and X⁴ are

Embodiment 85

A compound according to any one of embodiments 79 to 83, wherein

-   -   X³ is

and X¹ and X⁴ are

and X² is N. Embodiment 86

A compound according to any one of embodiments 79 to 83, wherein

-   -   X³ is

and X¹ and X² are

and X⁴ is N. Embodiment 87

A compound according to any one of embodiments 79 to 83, wherein

-   -   X³ is

and X² and X⁴ are

and X¹ is N. Embodiment 88

A compound according to any one of embodiments 79 to 83, wherein

-   -   X² is

and X¹, X³, and X⁴ are

Embodiment 89

A compound according to any one of embodiments 79 to 83, wherein

-   -   X² is

and X¹ and X⁴ are

and X³ is N. Embodiment 90

A compound according to any one of embodiments 79 to 83, wherein

-   -   X² is

and X¹ and X³ are

and X⁴ is N. Embodiment 91

A compound according to any one of embodiments 79 to 83, wherein

-   -   X² is

and X³ and X⁴ are

and X¹ is N. Embodiment 92

A compound according to any one of embodiments 79 to 83, wherein

-   -   X² is

and two of X¹, X³, and X⁴ are N.

Embodiment 93

A compound according to any one of embodiments 79 to 83, wherein

-   -   X³ is

and two of X¹, X², and X⁴ are N.

Embodiment 94

A compound according to any one of embodiments 79 to 83, wherein

-   -   X² is

and X¹, X³, and X⁴ are N.

Embodiment 95

A compound according to any one of embodiments 79 to 83, wherein

-   -   X³ is

and X¹, X², and X⁴ are N.

Embodiment 96

A compound according to any one of embodiments 79 to 95, wherein

-   -   v is 0, 1 or 2.

Embodiment 97

A compound according to any one of embodiments 79 to 95, wherein

-   -   v is 1 or 2.

Embodiment 98

A compound according to any one of embodiments 79 to 95, wherein

-   -   v is 1.

Embodiment 99

A compound according to any one of embodiments 79 to 95, wherein

-   -   v is 1, and R² is attached at either the 5-position or the        6-position of the benzothiazole ring.

Embodiment 100

A compound according to any one of embodiments 79 to 95, wherein

-   -   v is 1, and R² is attached at the 6-position of the        benzothiazole ring.

Embodiment 101

A compound according to any one of embodiments 79 to 95, wherein

-   -   v is 2, and one R² is attached at the 6-position of the        benzothiazole ring.

Embodiment 102

A compound according to any one of embodiments 79 to 95, wherein

-   -   v is 2, and R² is attached at the 5-position and the 6-position        of the benzothiazole ring.

Embodiment 103

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is -halogen, —C₁₋₆ alkyl, —CF₃, —OCF₃, —O—R^(f), or        —S(O)_(w)—R^(f), where the alkyl group is optionally substituted        one or more times with substituents independently selected from        R^(z).

Embodiment 104

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is -halogen, -methyl, ethyl, isopropyl, —OCH₃, —OCH₂CH₃,        —OCH(CH₃)₂, —CF₃, —OCF₃, —SCF₃, —S(O)₂—CH₃, —O-phenyl,        —O-(2-pyridyl), —O-(3-pyridyl), or —O-(4-pyridyl).

Embodiment 105

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is -halogen, -methyl, ethyl, isopropyl, —OCH₃, —OCH₂CH₃,        —OCH(CH₃)₂, —CF₃, —OCF₃, —SCF₃, —S(O)₂—CH₃, or —O-(3-pyridyl).

Embodiment 106

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is —Cl, —F, —CF₃, or —OCF₃.

Embodiment 107

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is —OCF₃.

Embodiment 108

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is —CF₃.

Embodiment 109

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is —F.

Embodiment 110

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is —Cl.

Embodiment 111

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is —SO₂CH₃.

Embodiment 112

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is methyl, ethyl, or isopropyl.

Embodiment 113

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is methyl.

Embodiment 114

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is —OCH₂CH₃.

Embodiment 115

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is —O-phenyl.

Embodiment 116

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is —O-(2-pyridyl), —O-(3-pyridyl), or —O-(4-pyridyl).

Embodiment 117

A compound according to any one of embodiments 79 to 102, wherein

-   -   R² is —O-(3-pyridyl).

Embodiment 118

A compound according to any one of embodiments 79 to 117, wherein

-   -   R⁴ is -methyl, -ethyl, -n-propyl, -isopropyl, -n-butyl,        -sec-butyl, -isobutyl, -tert-butyl, —(CH₂)₁₋₂—OCH₃, —(CH₂)₁₋₂—F,        —(CH₂)₁₋₂—Cl, —(CH₂)₁₋₂—OCF₃, —(CH₂)₁₋₂—NH₂, —(CH₂)₁₋₂—CN,        —(CH₂)₁₋₂—OH, —(CH₂)₁₋₂—CF₃, —(CH₂)₁₋₂—CO₂H, —(CH₂)₁₋₂—SH,        —(CH₂)₁₋₂—SCH₃, —(CH₂)₁₋₂—S(O)₂CH₃, —(CH₂)₁₋₂—OCH₂CH₃,        —(CH₂)₁₋₂—SCH₂CH₃, —(CH₂)₁₋₂—S(O)₂CH₂CH₃, —(CH₂)₁₋₂—NH—CH₃, or        —(CH₂)₁₋₂—N(CH₃)₂.

Embodiment 119

A compound according to any one of embodiments 79 to 117, wherein

-   -   R⁴ is -methyl, -ethyl, -isopropyl, -isobutyl, —CH₂CH₂—OCH₃,        —CH₂CH₂—F, —CH₂CH₂—NH₂, or —CH₂CH₂—NH—CH₃.

Embodiment 120

A compound according to any one of embodiments 79 to 117, wherein

-   -   R⁴ is -methyl, -ethyl, -isopropyl, or -isobutyl.

Embodiment 121

A compound according to any one of embodiments 79 to 117, wherein

-   -   R⁴ is methyl.

Embodiment 122

A compound according to any one of embodiments 79 to 117, wherein

-   -   R⁴ is -ethyl.

Embodiment 123

A compound according to any one of embodiments 79 to 117, wherein

-   -   R⁴ is -isopropyl.

Embodiment 124

A compound according to any one of embodiments 79 to 117, wherein

-   -   R⁴ is -isobutyl.

Embodiment 125

A compound according to any one of embodiments 79 to 117, wherein

-   -   R⁴ is —CH₂CH₂—OCH₃.

Embodiment 126

A compound according to any one of embodiments 79 to 117, wherein

-   -   R⁴ is —CH₂CH₂—F.

Embodiment 127

A compound according to any one of embodiments 79 to 117, wherein

-   -   R⁴ is —CH₂CH₂—NH₂.

Embodiment 128

A compound according to any one of embodiments 79 to 117, wherein

-   -   R⁴ is —CH₂CH₂—NH—CH₃.

Embodiment 129

A compound according to any one of embodiments 79 to 128, wherein

-   -   R¹ is independently hydrogen, —OCH₃, —F, —Cl, —NH₂, -cyano, —OH,        —CF₃, —OCF₃, —SH, —S—C₁₋₆ alkyl, —S(O)₂—C₁₋₆ alkyl, —CO₂H,        —NH—C₁₋₆ alkyl, —N(C₁₋₆ alkyl)₂, or —NH—C₁₋₆ alkyl.

Embodiment 130

A compound according to any one of embodiments 79 to 128, wherein

-   -   R¹ is independently —OCH₃, —F, —CF₃, —OCF₃, —N(CH₃)₂,        —N(CH₂CH₃)₂, or —N(CH₃)(CH₂CH₃).

Embodiment 131

A compound according to any one of embodiments 79 to 128, wherein

-   -   R¹ is independently hydrogen, —OCH₃, or —F.

Embodiment 132

A compound according to any one of embodiments 79 to 128, wherein

-   -   R¹ is hydrogen.

Embodiment 133

A compound according to any one of embodiments 79 to 128, wherein

-   -   R¹ is —F.

Embodiment 134

A compound according to any one of embodiments 79 to 128, wherein

-   -   R¹ is —OCH₃.

Embodiment 135

A compound according to any one of embodiments 79 to 128, wherein

-   -   R¹ is —N(CH₂CH₃)₂.

Embodiment 136

A compound according to any one of embodiments 79 to 135, wherein nomore than one R¹ substituent is not hydrogen.

Embodiment 137

A compound according to any one of embodiments 79 to 136, wherein

-   -   G is hydrogen, —C₁₋₈ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₆        alkylene-C₃₋₁₀ cycloaklyl, heterocyclyl, —C₁₋₆ alkylene-C₃₋₁₀        heterocyclyl, or NR^(h)R^(k), where the alkyl, alkylene,        cycloalkyl, and heterocyclyl groups are optionally substituted        one or more times with substituents independently selected from        R^(c); or G is —CH₂Y³, —CH₂CH₂Y³, —CH₂CH₂CH₂Y³, —CH(CH₃)CH₂Y³,        —CH₂CH(Y³)CH₃, —CH(Y³)CH₃, —CH₂C(Y³)(CH₃)₂, —C(Y³)(CH₃)₂, or

where Y³ is cyclopropyl, —CF₃, —OCF₃, —OCH₃, —OCH₂CH₃, —F, —Cl, —OH,—O(CH₂)₂—OH, —O(CH₂)₂—F, —SCH₃, —S(O)₂—CH₃, —SCH₂CH₃, —S(O)₂CH₂CH₃,—NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂, tetrahydropyran-4-yl,tetrahydrofuran-2-yl, morpholin-2-yl, morpholin-4-yl, piperidin-1-yl,4-hydroxy-piperidin-1-yl, 3-hydroxy-piperidin-1-yl, —NH—C(O)—CH₃,—NH—C(O)—CH₂CH₃, tetrahydrofuran-2-yl-methyloxy, or —C(O)—Y⁴, where Y⁴is —OH, —OCH₃, —OCH₂CH₃, —OC(CH₃)₃, —NH₂, —NH—CH₃, —NH—CH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, morpholin-4-yl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl,or piperazin-1-yl;

-   -   L is —CH₂—C(O)N(R⁶)—, —C(O)N(R⁶)—, —C(O)—O—, —SO₂—, —C(O)—, or        heterocyclylene optionally substituted one or more times with        substituents independently selected from R^(x); or the group        -L-G is -cyano;    -   R¹ is hydrogen or R^(a);    -   R^(c) is        -   a) -halogen,        -   b) —C₁₋₆ alkyl,        -   c) —C₃₋₁₀ cycloalkyl,        -   d) -heterocyclyl,        -   e) -cyano,        -   f) —CF₃,        -   g) —OCF₃,        -   h) —O—R^(h),        -   i) —S(O)_(w)—R^(h),        -   j) —S(O)₂O—R^(h),        -   k) —NR^(h)R^(k),        -   l) —C(O)—R^(h),        -   m) —C(O)—O—R^(h),        -   n) —OC(O)—R^(h),        -   o) —C(O)NR^(h)R^(k),        -   p) —C(O)-heterocyclyl,        -   q) —NR^(h)C(O)R^(k),        -   r) —OC(O)NR^(h)R^(k),        -   s) —NR^(h)C(O)OR^(k),        -   t) —NR^(h)C(O)NR^(h)R^(k),        -   u) —NR^(h)S(O)_(w)R^(k), or        -   v) —O—(C₁₋₄ alkylene)-O—(C₁₋₄ alkylene)-N(R^(h))C(O)—OR^(k),        -   where the alkylene, alkyl, cycloalkyl, and heterocyclyl            groups are optionally substituted one or more times with            substituents independently selected from R^(x);    -   R^(h) and R^(k) independently are hydrogen, C₁₋₆ alkyl, C₃₋₁₀        cycloalkyl, or heterocyclyl, where the alkyl, cycloalkyl, and        heterocyclyl groups are optionally substituted one or more times        with substituents independently selected from R^(x); or, if        R^(h) and R^(k) are both attached to the same nitrogen atom,        together with that nitrogen atom may optionally form a        heterocyclic ring selected from azetidino, pyrrolidino,        pyrazolidino, imidazolidino, oxazolidino, isoxazolidino,        thiazolidino, isothiazolidino, piperidino, piperazino,        morpholino, thiomorpholino, and azepano, where each ring is        optionally substituted one or more times with substituents        independently selected from R^(x); and    -   R^(x) is R^(y).

Embodiment 137

A compound according to any one of embodiments 79 to 136, wherein

-   -   L-G is not -cyano.

Embodiment 138

A compound according to any one of embodiments 79 to 136, wherein

-   -   L is —C(O)N(R⁶)—.

Embodiment 139

A compound according to embodiment 138 wherein

-   -   R⁶ is hydrogen.

Embodiment 140

A compound according to embodiment 138 wherein

-   -   R⁶ is methyl.

Embodiment 141

A compound according to embodiment 140 wherein

-   -   G is —N(CH₃)₂.

Embodiment 142

A compound according to any one of embodiments 79 to 136, wherein

-   -   L-G is —C(O)NR^(h)R^(k).

Embodiment 143

A compound according to embodiment 142, wherein

-   -   NR^(h)R^(k) is pyrrolidino, piperidino, piperazino,        4-methyl-piperazino, or morpholino, where each of the foregoing        is optionally substituted once with —(CH₂)₁₋₃—OH.

Embodiment 144

A compound according to embodiment 143, wherein

-   -   NR^(h)R^(k) is pyrrolidino, 4-(2-hydroxyethyl)-piperazino, or        4-(3-hydroxypropyl)-piperidino.

Embodiment 145

A compound according to embodiment 142, wherein

-   -   NR^(h)R^(k) is N[(CH₂)₂—OH]₂.

Embodiment 146

A compound according to any one of embodiments 79 to 137, wherein

-   -   L is not —CH₂—C(O)N(R⁶)—.

Embodiment 147

A compound according to any one of embodiments 79 to 146, wherein

-   -   L is not heterocyclylene.

Embodiment 148

A compound according to any one of embodiments 79 to 136, wherein

-   -   L is —S(O)₂—.

Embodiment 149

A compound according to embodiment 148, wherein

-   -   G is methyl or —CF₃.

Embodiment 150

A compound according to any one of embodiments 79 to 136, wherein

-   -   L is heteroarylene optionally substituted one or more times with        substituents independently selected from R^(x).

Embodiment 151

A compound according to embodiment 150, wherein

-   -   L-G is imidazol-2-yl, 1,2,4-triazol-3-yl, or        5-methyl-1,2,4-triazol-3-yl.

Embodiment 152

A compound according to any one of embodiments 79 to 136, wherein

-   -   L is —C(O)—O—.

Embodiment 153

A compound according to embodiment 152, wherein

-   -   G is hydrogen, or —C₁₋₈ alkyl, where the alkyl group is        optionally substituted one or more times with substituents        independently selected from R^(c).

Embodiment 154

A compound according to embodiment 153, wherein

-   -   G is methyl or ethyl.

Embodiment 155

A compound according to embodiment 153, wherein

-   -   G is hydrogen.

Embodiment 156

A compound according to any one of embodiments 79 to 139, wherein

-   -   G is —C₁₋₈ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₆ alkylene-C₃₋₁₀        cycloaklyl, heterocyclyl, or —C₁₋₆ alkylene-C₃₋₁₀ heterocyclyl,        where the alkyl, alkylene, cycloalkyl, and heterocyclyl groups        are optionally substituted one or more times with substituents        independently selected from R^(c).

Embodiment 157

A compound according to embodiment 156, wherein

-   -   G is —C₁₋₈ alkyl optionally substituted one or more times with        substituents independently selected from R^(c).

Embodiment 158

A compound according to embodiment 157, wherein

-   -   G is methyl, ethyl, isopropyl, n-propyl, n-butyl, sec-butyl, or        isobutyl.

Embodiment 159

A compound according to embodiment 157, wherein

-   -   G is methyl, ethyl, or n-propyl.

Embodiment 160

A compound according to embodiment 157, wherein

-   -   G is 2-fluoroethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl.

Embodiment 161

A compound according to embodiment 157, wherein

-   -   G is 2-cyanoethyl.

Embodiment 162

A compound according to embodiment 157, wherein

-   -   G is —C₁₋₈ alkyl substituted once by —C(O)—O—R^(h).

Embodiment 163

A compound according to embodiment 162, wherein

-   -   G is —CH₂—C(O)—O—R^(h).

Embodiment 164

A compound according to embodiment 163, wherein

-   -   R^(h) is hydrogen or methyl.

Embodiment 165

A compound according to embodiment 162, wherein

-   -   G is —CH₂CH₂—C(O)—O—R^(h).

Embodiment 166

A compound according to embodiment 165, wherein

-   -   R^(h) is hydrogen or methyl.

Embodiment 167

A compound according to embodiment 162, wherein

-   -   G is —C(CH₃)₂—C(O)—O—R^(h).

Embodiment 168

A compound according to embodiment 167, wherein

-   -   R^(h) is hydrogen or methyl.

Embodiment 169

A compound according to embodiment 162, wherein

-   -   G is —CH(CH₃)—C(O)—O—R^(h).

Embodiment 170

A compound according to embodiment 169, wherein

-   -   R^(h) is hydrogen or methyl.

Embodiment 171

A compound according to embodiment 157, wherein

-   -   G is —C₁₋₈ alkyl substituted once by —C(O)NR^(h)R^(k).

Embodiment 172

A compound according to embodiment 171, wherein

-   -   G is CH₂—C(O)—NR^(h)R^(k).

Embodiment 173

A compound according to embodiment 172, wherein

-   -   NR^(h)R^(k) is methylamino, dimethylamino, or diethylamino.

Embodiment 174

A compound according to embodiment 172, wherein

-   -   NR^(h)R^(k) is thiomorpholino or 1,1-dioxothiomorpholino.

Embodiment 175

A compound according to embodiment 172, wherein

-   -   NR^(h)R^(k) is morpholino, pyrrolidino, piperidino, piperazino,        or 4-methylpiperazino.

Embodiment 176

A compound according to embodiment 172, wherein

-   -   NR^(h)R^(k) is pyrrolidino, 3-hydroxy-pyrrolidino,        3-methoxy-pyrrolidino, 3-amino-pyrrolidino,        3-(methylamino)-pyrrolidino, 3-(dimethylamino)-pyrrolidino,        2-(hydroxymethyl)-pyrrolidino,        2-(dimethylaminocarbonyl)-pyrrolidino or        3,4-dihydroxy-pyrrolidino.

Embodiment 177

A compound according to embodiment 172, wherein

-   -   NR^(h)R^(k) is piperazino, 4-methylpiperazino,        4-(methylsulfonyl)-piperazino, or        4-(dimethylaminosulfonyl)-piperazino.

Embodiment 178

A compound according to embodiment 172, wherein

-   -   NR^(h)R^(k) is piperidino, 3-hydroxypiperidino,        4-hydroxypiperidino, 2-(hydroxymethyl)-piperidino,        3-(hydroxymethyl)-piperidino, 4-(hydroxymethyl)-piperidino,        3-methoxy-piperidino, 4-(methoxymethyl)-piperidino,        4-(fluoromethyl)-piperidino, 4-(trifluoromethyl)-piperidino,        4-cyano-piperidino, 4-carbamoyl-piperidino,        4-(methylamino)-piperidino, 4-(dimethylamino)-piperidino,        4-(methylaminomethyl)-piperidino, or        4-(dimethylaminomethyl)-piperidino.

Embodiment 179

A compound according to embodiment 172, wherein

-   -   NR^(h)R^(k) is NHR^(k), where R^(k) is 2-hydroxypropyl,        2-(methylsulfonyl)-ethyl, tetrahydrofuran-3-yl,        tetrahydropyran-4-yl, 1-methylpiperidin-4-yl, piperidin-3-yl, or        1-methylpiperidin-3-yl.

Embodiment 180

A compound according to embodiment 172, wherein

-   -   NR^(h)R^(k) is N(CH₃)R^(k), where R^(k) is 2-hydroxyethyl,        tetrahydropyran-4-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl,        or piperazin-3-yl.

Embodiment 181

A compound according to embodiment 172, wherein

-   -   NR^(h)R^(k) is N(CH₂CH₂OH)₂.

Embodiment 182

A compound according to embodiment 171, wherein

-   -   G is —(CH₂)₂₋₃—C(O)—N(CH₃)₂.

Embodiment 183

A compound according to embodiment 171, wherein

-   -   G is —(CH₂)₃—C(O)-(4-methylpiperazino).

Embodiment 184

A compound according to embodiment 171, wherein

-   -   G is —CH(CH₃)—C(O)—NR^(h)R^(k), where NR^(h)R^(k) is        methylamino, dimethylamino, 4-methylpiperazino, or morpholino.

Embodiment 185

A compound according to embodiment 171, wherein

-   -   G is —C(CH₃)₂—C(O)—N(CH₃)₂.

Embodiment 186

A compound according to embodiment 157, wherein

-   -   G is —CH—[C(O)—N(CH₃)₂]—[CH₂OH],        —CH—[C(O)—N(CH₃)₂]—[(CH₂)₄—NH₂], or        —CH—[C(O)—N(CH₃)₂]—[(CH₂)₄—N(CH₃)₂].

Embodiment 187

A compound according to embodiment 157, wherein

-   -   G is —C₁₋₈ alkyl substituted once by —O—R^(h).

Embodiment 188

A compound according to embodiment 187, wherein

-   -   G is —(CH₂)₂—O—R^(h).

Embodiment 189

A compound according to embodiment 188, wherein

-   -   R^(h) is hydrogen, methyl, or ethyl.

Embodiment 190

A compound according to embodiment 188, wherein

-   -   R^(h) is trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, or        2,2-difluoroethyl.

Embodiment 191

A compound according to embodiment 188, wherein

-   -   R^(h) is tetrahydrofuran-2-ylmethyl.

Embodiment 192

A compound according to embodiment 188, wherein

-   -   R^(h) is 2-hydroxyethyl.

Embodiment 193

A compound according to embodiment 188, wherein

-   -   R^(h) is 3-hydroxypropyl.

Embodiment 194

A compound according to embodiment 188, wherein

-   -   R^(h) is 2-methoxyethyl.

Embodiment 195

A compound according to embodiment 188, wherein

-   -   R^(h) is 2-(2-hydroxyethoxy)-ethyl.

Embodiment 196

A compound according to embodiment 188, wherein

-   -   R^(h) is 2-hydroxypropyl or 1-hydroxyprop-2-yl.

Embodiment 197

A compound according to embodiment 188, wherein

-   -   R^(h) is 2-cyanoethyl, 2-(methylcarbonylamino)-ethyl, or        2-(methylsulfonylamino)-ethyl.

Embodiment 198

A compound according to embodiment 188, wherein

-   -   R^(h) is 2-aminoethyl, 2-(methylamino)-ethyl, or        2-(dimethylamino)-ethyl.

Embodiment 199

A compound according to embodiment 188, wherein

-   -   R^(h) is carbamoylmethyl.

Embodiment 200

A compound according to embodiment 187, wherein

-   -   G is —(CH₂)₃—O—R^(h).

Embodiment 201

A compound according to embodiment 200, wherein

-   -   R^(h) is hydrogen, methyl, or ethyl.

Embodiment 202

A compound according to embodiment 200, wherein

-   -   R^(h) is 2-hydroxyethyl.

Embodiment 203

A compound according to embodiment 187, wherein

-   -   G is —(CH2)₄—OH, —(CH2)₅—OH, —CH₂C(CH₃)₂—OH, —CH₂C(CH₃)₂—OCH₃,        —CH₂C(CH₃)₂—CH₂—OH, —CH(CH₃)—CH₂—OCH₃, —(CH₂)₃C(CH₃)₂—CH₂—OH,        —(CH₂)₂CH(CH₃)—CH₂—OH, or —(CH₂)₂CH(CH₃)—OH.

Embodiment 204

A compound according to embodiment 187, wherein

-   -   G is —CH₂CH(CH₃)—O—R^(h).

Embodiment 205

A compound according to embodiment 204, wherein

-   -   R^(h) is hydrogen, methyl, or ethyl.

Embodiment 206

A compound according to embodiment 157, wherein

-   -   G is —CH₂—CH(OH)—CH₂—OH.

Embodiment 207

A compound according to embodiment 157, wherein

-   -   G is —C₁₋₈ alkyl substituted once by —NR^(h)R^(k).

Embodiment 208

A compound according to embodiment 207, wherein

-   -   G is —(CH₂)₂—NR^(h)R^(k).

Embodiment 209

A compound according to embodiment 208, wherein

-   -   NR^(h)R^(k) is amino, methylamino, or dimethylamino.

Embodiment 210

A compound according to embodiment 208, wherein

-   -   NR^(h)R^(k) is methylcarbonylamino.

Embodiment 211

A compound according to embodiment 208, wherein

-   -   NR^(h)R^(k) is (dimethylamino)methylcarbonylamino,        hydroxymethylcarbonylamino, or 1-hydroxyethylcarbonylamino.

Embodiment 212

A compound according to embodiment 208, wherein

-   -   NR^(h)R^(k) is methylsulfonylamino.

Embodiment 213

A compound according to embodiment 208, wherein

-   -   NR^(h)R^(k) is piperidino, 4-hydroxypiperidino, or        3-hydroxypiperidino.

Embodiment 214

A compound according to embodiment 208, wherein

-   -   NR^(h)R^(k) is piperidino, 4,4-difluoropiperidino, or        3,3-difluoropiperidino.

Embodiment 215

A compound according to embodiment 208, wherein

-   -   NR^(h)R^(k) is 2-oxo-pyrrolidino, 2-oxo-imidazolidino, or        3-oxo-piperazino.

Embodiment 216

A compound according to embodiment 208, wherein

-   -   NR^(h)R^(k) is piperazino, 4-methylpiperazino, morpholino, or        1,1-dioxothiomorpholino.

Embodiment 217

A compound according to embodiment 207, wherein

-   -   G is —(CH₂)₃—NR^(h)R^(k).

Embodiment 218

A compound according to embodiment 217, wherein

-   -   NR^(h)R^(k) is amino, dimethylamino, or diethylamino.

Embodiment 219

A compound according to embodiment 217, wherein

-   -   NR^(h)R^(k) is piperidino, 4-methylpiperazino, or morpholino.

Embodiment 220

A compound according to embodiment 207, wherein

-   -   G is —(CH₂)₄—NR^(h)R^(k).

Embodiment 221

A compound according to embodiment 220, wherein

-   -   NR^(h)R^(k) is amino, dimethylamino, or diethylamino.

Embodiment 222

A compound according to embodiment 156, wherein

-   -   G is —C₁₋₆ alkylene-heterocyclyl, where the alkylene and        heterocyclyl groups are optionally substituted one or more times        with substituents independently selected from R^(c).

Embodiment 223

A compound according to embodiment 222, wherein

-   -   G is —CH₂-heterocyclyl, where the heterocyclyl group is        optionally substituted once with a substituent selected from        R^(c).

Embodiment 224

A compound according to embodiment 223, wherein

-   -   the heterocyclyl group is tetrahydropyran-4-yl,        tetrahydrofuran-2-yl, 1,4-dioxan-2-yl, morpholin-2-yl,        tetrahydropyran-2-yl, piperidin-4-yl,        1-(2-hydroxyethyl)-piperidin-4-yl,        1-(dimethylaminomethylcarbonyl)-piperidin-4-yl, piperazin-2-yl,        or 1-methyl-piperazin-2-yl.

Embodiment 225

A compound according to embodiment 156, wherein

-   -   G is C₃₋₁₀ cycloalkyl optionally substituted one or more times        with substituents independently selected from R^(c).

Embodiment 226

A compound according to embodiment 225, wherein

-   -   G is 4-hydroxy-cyclohexyl, 4-carboxy-cyclohexyl, or        4-(dimethylaminocarbonyl)-cyclohexyl.

Embodiment 227

A compound according to embodiment 225, wherein

-   -   G is 1-carboxy-cyclopropyl, 1-(ethoxycarbonyl)-cyclopropyl, or        1-(dimethylamino-carbonyl)-cyclopropyl.

Embodiment 228

A compound according to embodiment 156, wherein

-   -   G is C₁₋₆ alkylene-C₃₋₁₀ cycloalkyl, where the alkylene and        cycloalkyl groups are optionally substituted one or more times        with substituents independently selected from R^(c).

Embodiment 229

A compound according to embodiment 228, wherein

-   -   G is —CH₂-(4-hydroxy-cyclohexyl).

Embodiment 230

A compound according to embodiment 228, wherein

-   -   G is —(CH₂)₂-(4-hydroxy-cyclohexyl).

Embodiment 231

A compound according to embodiment 228, wherein

-   -   G is —CH₂-[4-(hydroxymethyl)-cyclohexyl].

Embodiment 232

A compound according to embodiment 156, wherein

-   -   G is heterocyclyl optionally substituted one or more times with        substituents independently selected from R^(c).

Embodiment 233

A compound according to embodiment 232, wherein

-   -   G is piperidin-4-yl, 1-methyl-piperidin-4-yl,        1-carboxy-piperidin-4-yl, 1-(methylsulfonyl)-piperidin-4-yl,        1-(2-hydroxyethyl)-piperidin-4-yl,        1-(dimethyl-aminocarbonyl)piperidin-4-yl, or        1-(dimethylaminomethylcarbonyl)-piperidin-4-yl.

Embodiment 234

A compound according to embodiment 232, wherein

-   -   G is piperidin-3-yl or        1-(dimethylaminomethylcarbonyl)-piperidin-3-yl.

Embodiment 235

A compound according to embodiment 232, wherein

-   -   G is 1,1-dioxo-tetrahydrothiophen-3-yl.

Embodiment 236

A compound according to embodiment 232, wherein

-   -   G is pyrrolidin-3-yl, 1-methyl-pyrrolidin-3-yl,        1-(2-hydroxyethyl)-pyrrolidin-3-yl,        1-(2-hydroxypropyl)-pyrrolidin-3-yl,        1-(2-hydroxy-2-methylpropyl)-pyrrolidin-3-yl,        1-(1-hydroxyethylcarbonyl)-pyrrolidin-3-yl,        1-(2-carboxyethyl)-pyrrolidin-3-yl, or        1-(2-methylsulfonylamino-ethyl)-pyrrolidin-3-yl.

Embodiment 237

A compound according to embodiment 157, wherein

-   -   G is —C₁₋₈ alkyl substituted once by —S—R^(h).

Embodiment 238

A compound according to embodiment 237, wherein

-   -   G is —(CH₂)₂—S—R^(h).

Embodiment 239

A compound according to embodiment 238, wherein

-   -   R^(h) is methyl or ethyl.

Embodiment 240

A compound according to embodiment 238, wherein

-   -   R^(h) is 2-hydroxyethyl.

Embodiment 241

A compound according to embodiment 237, wherein

-   -   G is —(CH₂)₃—S—R^(h).

Embodiment 242

A compound according to embodiment 241, wherein

-   -   R^(h) is methyl.

Embodiment 243

A compound according to embodiment 157, wherein

-   -   G is —C₁₋₈ alkyl substituted once by —SO₂—R^(h).

Embodiment 244

A compound according to embodiment 243, wherein

-   -   G is —(CH₂)₂—SO₂—R^(h).

Embodiment 245

A compound according to embodiment 244, wherein

-   -   R^(h) is methyl or ethyl.

Embodiment 246

A compound according to embodiment 244, wherein

-   -   R^(h) is 2-hydroxyethyl.

Embodiment 247

A compound according to embodiment 243, wherein

-   -   G is —(CH₂)₃—SO₂—R^(h).

Embodiment 248

A compound according to embodiment 247, wherein

-   -   R^(h) is methyl.

Embodiment 249

A compound according to embodiment 156 wherein

-   -   G is —CH(CH₃)—NR^(h)R^(k), where NR^(h)R^(k) is pyrrolidino,        piperidino, 4-methyl-piperazino, morpholino, or dimethylamino.

Embodiment 250

A compound according to embodiment 156 wherein

-   -   G is 1-(2-hydroxypropyl)-pyrrolidin-3-yl or        1-(1-hydroxyethylcarbonyl)-pyrrolidin-3-yl.

Embodiment 251

A compound according to embodiment 156 wherein

-   -   G is 1-(dimethylaminomethylcarbonyl)-piperidin-4-yl.

Embodiment 252

A compound according to embodiment 156 wherein

-   -   G is —(CH₂)₃₋₅—OH.

Embodiment 253

A compound according to embodiment 156 wherein

-   -   G is 4-hydroxy-cyclohexylmethyl.

Embodiment 254

A compound according to embodiment 156 wherein

-   -   G is —(CH₂)₂—NHC(O)—CH₂—N(CH₃)₂.

Embodiment 255

A compound according to embodiment 156 wherein

-   -   G is 4-hydroxy-cyclohexylmethyl.

Embodiment 256

A compound according to embodiment 156 wherein

-   -   G is —CH₂—C(O)—NR^(h)R^(k), where NR^(h)R^(k) is        3-hydroxy-pyrrolidino or 3-(dimethyl-amino)-pyrrolidino.

Embodiment 257

A compound according to embodiment 156 wherein

-   -   G is —CH₂—C(O)—NR^(h)R^(k), where NR^(h)R^(k) is morpholino.

Embodiment 258

A compound according to embodiment 156 wherein

-   -   G is —CH₂—C(O)—NR^(h)R^(k), where NR^(h)R^(k) is        4-hydroxy-piperidino, 4-methoxy-piperidino,        4-(hydroxymethyl)-piperidino, 3-hydroxy-piperidino,        3-methoxy-piperidino, 3-(hydroxymethyl)-piperidino, or        4,4-difluoropiperidino.

Embodiment 259

A compound according to embodiment 156 wherein

-   -   G is —CH₂—C(O)—NR^(h)R^(k), where NR^(h)R^(k) is dimethylamino.

Embodiment 260

A compound according to embodiment 156 wherein

-   -   G is —(CH₂)₂—O—(CH₂)₂—OH.

Embodiment 261

A compound according to embodiment 156 wherein

-   -   G is —(CH₂)₂—O—(CH₂)₂—OCH₃.

Embodiment 262

A compound according to embodiment 156 wherein

-   -   G is —CH₂—CH(CH₃)—OH.

Embodiment 263

A compound according to any one of embodiments 79 to 136, wherein

-   -   L is C(O)NH, and G is C₁₋₈ alkyl substituted once by a        heteroaryl group, where the heteroaryl group is optionally        substituted one or more times with substituents independently        selected from R^(x).

Embodiment 264

A compound according to embodiment 263, wherein

-   -   G is —CH₂-(2-furyl), —CH₂-(2-thienyl), —CH₂-(2-oxazolyl), or        —CH₂-(2-thiazolyl).

Embodiment 265

A compound according to embodiment 263, wherein

-   -   G is —(CH₂)₂₋₃-(1-pyrrolyl), —(CH₂)₂₋₃-(1-pyrazolyl), or        —(CH₂)₂₋₃-(1-imidazolyl).

Embodiment 266

A compound according to any one of embodiments 79 to 136, wherein

-   -   L is C(O)NH, and G is C₁₋₈ alkyl substituted once by a phenyl        group, where the phenyl group is optionally substituted one or        more times with substituents independently selected from R^(x).

Embodiment 267

A compound according to embodiment 266, wherein

-   -   G is —(—CH₂)₁₋₂-(4-hydroxyphenyl) or        —(—CH₂)₁₋₂-(4-methoxy-3-hydroxyphenyl).

Embodiment 268

A compound according to any one of embodiments 79 to 136, wherein

-   -   L is C(O)NH, and G is —CH₂—C(O)NH—CH₂-(4-hydroxyphenyl).

Embodiment 269

A compound according to any one of embodiments 79 to 136, wherein

-   -   L is C(O)NH, and G is        —CH₂—C(O)-[4-(pyrimidin-2-yloxy)-piperidino].

Embodiment 270

A compound according to any one of embodiments 1 to 269, wherein thecompound is in the form of a free acid or a free base.

Embodiment 271

A compound according to any one of embodiments 1 to 269, wherein thecompound is in the form of a pharmaceutically acceptable salt.

The routes in the Examples illustrate methods of synthesizing compoundsof Formula (I), or a pharmaceutically acceptable salt thereof. Theskilled artisan will appreciate that the compounds of the inventioncould be made by methods other than those specifically described herein,by adaptation of the methods described herein and/or adaptation thereof,for example by methods known in the art.

Examples of compounds of Formula (I) or pharmaceutically acceptablesalts thereof having useful biological activity are listed the Examplessection and in Table 1. The ability of compounds of Formula (I) orpharmaceutically acceptable salts thereof to increase levels or activityof HMOX1 was established using the Biological Assay described below. Inthe chemical structures shown below, standard chemical abbreviations aresometimes used. Including Me=methyl, Et=ethyl, OMe=methyoxy,OEt=ethyoxy, and the like. Note that, in some instances, the name mayrecite a salted form of the compound. In these instances, the saltedform of the compound was made, even if the corresponding structure maynot show the presence of the counterion. For compounds that were made inthe form of a hydrochloride salt, no names or structures are intended torecite any particular stoichiometric relationship between counterions.

TABLE 1 No. Structure Name 1

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methyl amide 2

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methyl ester 3

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid 4

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-ethoxy- ethyl)-amide 5

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid cyclopropylmethyl-amide 6

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ethylamide 7

[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazol-5-yl]- pyrrolidin-1-yl-methanone 8

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methoxy-ethyl)-amide 9

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-fluoro- ethyl)-amide 10

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- hydroxy-ethyl)-amide 11

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3-pyrazol- 1-yl-propyl)-amide 12

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid propylamide 13

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3- hydroxy-propyl)-amide 14

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3-ethoxy- propyl)-amide 15

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid morpholin- 4-ylamide 16

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2,2,2- trifluoro-ethyl)-amide 17

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide 18

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (tetrahydro-furan-2-ylmethyl)-amide 19

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3- methoxy-propyl)-amide 20

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methoxy-1-methyl-ethyl)- amide21

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- hydroxy-propyl)-amide 22

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methoxy-2-methyl- propyl)-amide23

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methyl ester 24

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid 25

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methoxy-ethyl)-amide 26

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ethylamide 27

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- hydroxy-ethyl)-amide 28

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid methyl ester 29

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid 30

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2- hydroxy-ethyl)-amide 31

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2- methoxy-ethyl)-amide 32

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid ethylamide 33

2-(5,6-Difluoro- benzothiazol-2-ylamino)- 1-methyl-1H- benzoimidazole-5-carboxylic acid methyl ester 34

2-(5,6-Difluoro- benzothiazol-2-ylamino)- 1-methyl-1H- benzoimidazole-5-carboxylic acid 35

2-(5,6-Difluoro- benzothiazol-2-ylamino)- 1-methyl-1H- benzoimidazole-5-carboxylic acid ethylamide 36

2-(5,6-Difluoro- benzothiazol-2-ylamino)- 1-methyl-1H- benzoimidazole-5-carboxylic acid (2- hydroxy-ethyl)-amide 37

2-(5,6-Difluoro- benzothiazol-2-ylamino)- 1-methyl-1H- benzoimidazole-5-carboxylic acid (2- methoxy-ethyl)-amide 38

3-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-3H-benzoimidazole-5- carboxylic acid methylamide 39

6-Fluoro-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methoxy-ethyl)-amide 40

6-Fluoro-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methyl ester 41

6-Fluoro-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid 42

6-Fluoro-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ethylamide 43

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- morpholin-4-yl-ethyl)- amide 44

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- trifluoromethoxy-ethyl)- amide45

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- hydroxy-2-methyl-propyl)- amide46

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- hydroxy-ethoxy)-ethyl]-amide 47

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- fluoro-ethoxy)-ethyl]- amide48

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (furan-2- ylmethyl)-amide 49

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ([1,4]dioxan-2-ylmethyl)- amide 50

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((S)-2- hydroxy-propyl)-amide 51

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((R)-2- hydroxy-propyl)-amide 52

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (trans-4- hydroxy-cyclohexyl)-amide 53

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2- (tetrahydro-furan-2-ylmethoxy)-ethyl]-amide 54

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-ethoxy- propyl)-amide 55

2-({[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carbonyl]-amino}-methyl)- morpholine-4-carboxylicacid tert-butyl ester 56

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (morpholin-2-ylmethyl)- amidehydrochloride 57

6-Fluoro-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-ethoxy- ethyl)-amide 58

6-Fluoro-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid dimethylcarbamoylmethyl- amide 59

6-Fluoro-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- morpholin-4-yl-ethyl)- amide 60

6-Fluoro-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- hydroxy-propyl)-amide 61

6-Methoxy-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methyl ester 62

6-Methoxy-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid 63

6-Methoxy-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid dimethylcarbamoyl- methyl-amide 64

6-Methoxy-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ethylamide 65

6-Methoxy-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-ethoxy- ethyl)-amide 66

6-Methoxy-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- morpholin-4-yl-ethyl)- amide 67

6-Methoxy-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methoxy-ethyl)-amide 68

6-Methoxy-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- hydroxy-propyl)-amide 69

6-Diethylamino-1-methyl- 2-(6-trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methyl ester 70

6-Diethylamino-1-methyl- 2-(6-trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid 71

3-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-3H-imidazo[4,5- b]pyridine-6-carboxylic acid ethyl ester 72

3-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-3H-imidazo[4,5- b]pyridine-6-carboxylic acid 73

3-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-3H-imidazo[4,5- b]pyridine-6-carboxylic acid (2-methoxy-ethyl)- amide 74

3-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-3H-imidazo[4,5- b]pyridine-6-carboxylic acid dimethylcarbamoylmethyl-amide 75

3-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-3H-imidazo[4,5- b]pyridine-6-carboxylic acid (2-ethoxy-ethyl)- amide 76

3-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-3H-imidazo[4,5- b]pyridine-6-carboxylic acid ethylamide 77

3-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-3H-imidazo[4,5- b]pyridine-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide 78

3-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-3H-imidazo[4,5- b]pyridine-6-carboxylic acid (2-hydroxy-propyl)- amide79

{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carbonyl]-amino}-acetic acid methyl ester 80

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid dimethylcarbamoylmethyl- amide 81

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((S)-1- ethylcarbamoyl-ethyl)-amide 82

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- dimethylamino-ethyl)- amide 83

{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carbonyl]-amino}-acetic acid 84

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methylamide 85

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-ethoxy- ethyl)-amide 86

2-(5,6-Difluoro- benzothiazol-2-ylamino)- 1-methyl-1H- benzoimidazole-5-carboxylic acid methylamide 87

2-(5,6-Difluoro- benzothiazol-2-ylamino)- 1-methyl-1H- benzoimidazole-5-carboxylic acid (2-ethoxy- ethyl)-amide 88

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid methylamide 89

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2-ethoxy- ethyl)-amide 90

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (1- methanesulfonyl-piperidin-4-yl)-amide 91

{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carbonyl]-amino}-acetic acid tert-butyl ester 92

4-{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carbonyl]-amino}- piperidine-1-carboxylic acidtert-butyl ester 93

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid piperidin- 4-ylamide hydrochloride94

3-{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carbonyl]-amino}- piperidine-1-carboxylic acidtert-butyl ester 95

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid piperidin- 3-ylamide hydrochloride96

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (thiazol-2- ylmethyl)-amide 97

3-{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carbonyl]-amino}- propionic acid methyl ester 98

3-{[2-(6-Trifluoromethoxy- benzothiazol-2-ylamino)- 1-methyl-1H-benzimidazole-5- carbonyl]-amino}- propionic acid 99

1-Methyl-2-(5- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methyl ester 100

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- acetylamino-ethyl)-amide 101

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methylsulfanyl-ethyl)- amide102

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methanesulfonyl-ethyl)- amide103

(2-{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carbonyl]-amino}-ethyl)- carbamic acid tert-butylester 104

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-amino- ethyl)-amidehydrochloride 105

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methylamino-ethyl)-amide 106

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid trimethylhydrazide 107

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- ethylsulfanyl-ethyl)-amide 108

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3- methylsulfanyl-propyl)- amide109

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid (2- ethanesulfonyl-ethyl)- amide 110

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid (3- methanesulfonyl-propyl)- amide111

2-(5-Fluoro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid methyl ester 112

2-(6-Fluoro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid methyl ester 113

2-(6-Methanesulfonyl- benzothiazol-2-ylamino)- 1-methyl-1H-benzoimidazole-5- carboxylic acid methyl ester 114

1-Methyl-2-(6-methyl- benzothiazol-2-ylamino)- 1H-benzoimidazole-5-carboxylic acid methyl ester 115

1-Methyl-2-(5- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid methylamide 116

1-Methyl-2-(5- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid (2- methoxy-ethyl)-amide 117

2-(5-Fluoro-benzothiazol- 2-ylamino)-1-methyl-1H- benzimidazole-5-carboxylic acid 118

2-(6-Fluoro-benzothiazol- 2-ylamino)-1-methyl-1H- benzimidazole-5-carboxylic acid 119

2-(6-Methanesulfonyl- benzothiazol-2-ylamino)- 1-methyl-1H-benzimidazole-5- carboxylic acid 120

1-Methyl-2-(6-methyl- benzothiazol-2-ylamino)- 1H-benzimidazole-5-carboxylic acid 121

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid (1,1-dioxo- tetrahydro-1λ⁶-thiophen-3-yl)-amide 122

2-(5-Fluoro-benzothiazol- 2-ylamino)-1-methyl-1H- benzimidazole-5-carboxylic acid methylamide 123

2-(5-Fluoro-benzothiazol- 2-ylamino)-1-methyl-1H- benzimidazole-5-carboxylic acid (2- methoxy-ethyl)-amide 124

2-(6-Fluoro-benzothiazol- 2-ylamino)-1-methyl-1H- benzimidazole-5-carboxylic acid methylamide 125

2-(6-Fluoro-benzothiazol- 2-ylamino)-1-methyl-1H- benzimidazole-5-carboxylic acid (2- methoxy-ethyl)-amide 126

2-(6-Methanesulfonyl- benzothiazol-2-ylamino)- 1-methyl-1H-benzimidazole-5- carboxylic acid methylamide 127

2-(6-Methanesulfonyl- benzothiazol-2-ylamino)- 1-methyl-1H-benzimidazole-5- carboxylic acid (2- methoxy-ethyl)-amide 128

2-(6-Methyl-benzothiazol- 2-ylamino)-1-methyl-1H- benzimidazole-5-carboxylic acid methylamide 129

2-(6-Methyl-benzothiazol- 2-ylamino)-1-methyl-1H- benzimidazole-5-carboxylic acid (2- methoxy-ethyl)-amide 130

2-(6-Methanesulfonyl- benzothiazol-2-ylamino)- 1-methyl-1H-benzimidazole-5- carboxylic acid (2- methylsulfanyl-ethyl)- amide 131

2-(6-Methanesulfonyl- benzothiazol-2-ylamino)- 1-methyl-1H-benzimidazole-5- carboxylic acid (2- methylsulfonyl-ethyl)- amide 132

1-Methyl-2-(6- trifluoromethylsulfanyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methyl ester 133

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzimidazole-5-carboxylic acid dimethylcarbamoylmethyl- amide 134

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid dimethylcarbamoylmethyl- amide 135

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid (2- dimethylcarbamoyl-ethyl)- amide136

3-{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carbonyl]-amino}- propionic acid tert-butyl ester137

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid [2-(4- methyl-piperazin-1-yl)-2-oxo-ethyl]-amide 138

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid (2- morpholin-4-yl-2-oxo-ethyl)-amide 139

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid methylcarbamoylmethyl- amide 140

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid diethylcarbamoylmethyl- amide 141

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid (2-oxo-2- pyrrolidin-1-yl-ethyl)-amide 142

4-(2-{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carbonyl]-amino}-acetyl)- piperazine-1-carboxylicacid tert-butyl ester 143

(S)-2-{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carbonyl]-amino}- propionic acid methyl ester 144

1-{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carbonyl]-amino}- cyclopropanecarboxylic acid ethylester 145

2-Methyl-2-{[1-methyl-2- (6-trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carbonyl]-amino}- propionic acid methyl ester 146

(S)-2-{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carbonyl]-amino}- propionic acid 147

1-{[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carbonyl]-amino}- cyclopropanecarboxylic acid 148

2-Methyl-2-{[1-methyl-2- (6-trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carbonyl]-amino}- propionic acid 149

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((S)-1- dimethylcarbamoyl-ethyl)-amide 150

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid (1- dimethylcarbamoyl-cyclopropyl)-amide 151

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid (1- dimethylcarbamoyl-1-methyl-ethyl)-amide 152

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzimidazole-5- carboxylic acid (2-oxo-2- piperazin-1-yl-ethyl)-amide hydrochloride 153

1-Ethyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methyl ester 154

1-Ethyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid 155

1-Ethyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methylamide 156

1-Ethyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ethylamide 157

1-Ethyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-ethoxy- ethyl)-amide 158

1-Isopropyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)- 1Hbenzoimidazole-5- carboxylic acid methyl ester 159

1-Isopropyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid 160

1-Isopropyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methylamide 161

1-Isopropyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ethylamide 162

1-Isobutyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methyl ester 163

1-Isobutyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid 164

1-Isobutyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methylamide 165

1-Isobutyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ethylamide 166

1-(2-Methoxy-ethyl)-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid 167

1-(2-Methoxy-ethyl)-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methylamide 168

1-(2-Methoxy-ethyl)-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methoxy-ethyl)-amide 169

1-(2-Methoxy-ethyl)-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-ethoxy- ethyl)-amide 170

1-(2-Fluoro-ethyl)-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methylamide 171

1-(2-Fluoro-ethyl)-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methoxy-ethyl)-amide 172

1-(2-Fluoro-ethyl)-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-ethoxy- ethyl)-amide 173

1-(2-Amino-ethyl)-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methylamide hydrochloride 174

2-(6-Chloro-benzothiazol- 2-ylamino)-1-ethyl-1H- benzoimidazole-5-carboxylic acid methylamide 175

2-(6-Chloro-benzothiazol- 2-ylamino)-1-ethyl-1H- benzoimidazole-5-carboxylic acid ethylamide 176

2-(6-Chloro-benzothiazol- 2-ylamino)-1-ethyl-1H- benzoimidazole-5-carboxylic acid (2-fluoro- ethyl)-amide 177

2-(6-Chloro-benzothiazol- 2-ylamino)-1-ethyl-1H- benzoimidazole-5-carboxylic acid (2- methoxy-ethyl)-amide 178

2-(6-Chloro-benzothiazol- 2-ylamino)-1-ethyl-1H- benzoimidazole-5-carboxylic acid (2- methoxy-2-methyl- propyl)-amide 179

2-(6-Chloro-benzothiazol- 2-ylamino)-1-ethyl-1H- benzoimidazole-5-carboxylic acid (2-ethoxy- ethyl)-amide 180

1-Ethyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole- 5-carboxylic acid methylamide 181

1-Ethyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ethylamide 182

1-Ethyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methoxy-ethyl)-amide 183

1-Ethyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-ethoxy- ethyl)-amide 184

1-Ethyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methoxy-2-methyl- propyl)-amide185

1-Ethyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methylsulfanyl-ethyl)- amide186

1-Ethyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid dimethylcarbamoylmethyl- amide 187

1-Ethyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid dimethylcarbamoylmethyl- amide 188

1-(2-Methoxy-ethyl)-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid dimethylcarbamoylmethyl- amide 189

1-(2-Methoxy-ethyl)-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- methyl-piperazin-1-yl)-2-oxo-ethyl]-amide 190

1-Ethyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- methyl-piperazin-1-yl)-2-oxo-ethyl]-amide 191

1-Ethyl-2-[6-(pyridin-3- yloxy)-benzothiazol-2- ylamino]-1H-benzoimidazole-5- carboxylic acid (2- methoxy-ethyl)-amide 192

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- hydroxy-piperidin-1-yl)-ethyl]-amide 193

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(3- hydroxy-piperidin-1-yl)-ethyl]-amide 194

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carbonitrile 195

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-6- carbonitrile 196

[5-(1H-Imidazol-2-yl)-1- methyl-1H-benzimidazol-2-yl]-(6-trifluoromethoxy- benzothiazol-2-yl)-amine 197

[1-Methyl-6-(1H-1,2,4- triazol-3-yl)-1H- benzimidazol-2-yl]-(6-trifluoromethoxy- benzothiazol-2-yl)-amine 198

[1-Methyl-6-(5-methyl-1H- 1,2,4-triazol-3-yl)-1H- benzimidazol-2-yl]-(5-trifluoromethoxy- benzothiazol-2-yl)-amine 199

(1-Ethyl-5- trifluoromethanesulfonyl- 1H-benzoimidazol-2-yl)-(6-trifluoromethoxy- benzothiazol-2-yl)-amine 200

1-[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazol-5-yl]- ethanone 201

(5-Methanesulfonyl-1- methyl-1H-benzoimidazol-2-yl)-(6-trifluoromethoxy- benzothiazol-2-yl)-amine 202

2-[1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazol-6-yl]- acetamide 203

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid ((R)-2- hydroxy-propyl)-amide 204

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid ((S)-2- hydroxy-propyl)-amide 205

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((R)-2- hydroxy-propyl)-amide 206

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((S)-2- hydroxy-propyl)-amide 207

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2- methoxy-2-methyl- propyl)-amide 208

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methoxy-2-methyl- propyl)-amide209

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2-fluoro- ethyl)-amide 210

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-fluoro- ethyl)-amide 211

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid cyanomethyl-amide 212

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-cyano- ethyl)-amide 213

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2-cyano- ethyl)-amide 214

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (3- hydroxy-propyl)-amide 215

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (3- hydroxy-butyl)-amide 216

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3- hydroxy-butyl)-amide 217

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3- hydroxy-2,2-dimethyl-propyl)-amide 218

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (3- hydroxy-2,2-dimethyl- propyl)-amide 219

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (4- hydroxy-butyl)-amide 220

2-(6-Chloro-1H- benzoimidazol-2- ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (4- hydroxy-butyl)-amide 221

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (4- hydroxy-butyl)-amide 222

6-Fluoro-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (4- hydroxy-butyl)-amide 223

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((R)-4- hydroxy-3-methyl-butyl)-amide 224

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid ((R)-4- hydroxy-3-methyl-butyl)- amide 225

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (trans-4- hydroxy-cyclohexyl)- amide 226

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (5- hydroxy-pentyl)-amide 227

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (5- hydroxy-pentyl)-amide 228

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (5- hydroxy-pentyl)-amide 229

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (5- hydroxy-4,4-dimethyl-pentyl)-amide 230

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid 4-hydroxy- benzylamide 231

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid 3-hydroxy- 4-methoxy-benzylamide232

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (trans-A- hydroxy-cyclohexylmethyl)-amide 233

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (trans-4- hydroxy- cyclohexylmethyl)-amide 234

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (trans-A- hydroxy-cyclohexylmethyl)-amide 235

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(2- hydroxy-ethoxy)-ethyl]- amide 236

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- hydroxy-ethoxy)-ethyl]-amide 237

6-Fluoro-1-methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- hydroxy-ethoxy)-ethyl]-amide 238

3-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-3H-imidazo[4,5- b]pyridine-6-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide 239

1-(2-Methylamino-ethyl) 2-(6-trifluoromethoxy- benzothiazol-2 ylamino)1H-benzoimidazole-5- carboxylic acid[2-(2- hydroxy-ethoxy)-ethyl]- amidehydrochloride 240

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2- methylamino-ethyl)-1H-benzoimidazole-5- carboxylic acid [2-(2- hydroxy-ethoxy)-ethyl]- amidehydrochloride 241

1-(2-Methoxy-ethyl)-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- hydroxy-ethoxy)-ethyl]-amide 242

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((R)-2-hydroxy-1-methyl-ethoxy)- ethyl]-amide 243

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-((R)-2- hydroxy-1-methyl-ethoxy)- ethyl]-amide 244

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- hydroxy-propoxy)-ethyl]-amide 245

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- hydroxy-2-methyl-propoxy)-ethyl]-amide 246

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(3- hydroxy-propoxy)-ethyl]-amide 247

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(3- fluoro-propoxy)-ethyl]-amide 248

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(3- hydroxy-propoxy)-ethyl]- amide 249

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(3- fluoro-propoxy)-ethyl]- amide 250

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [3-(2- hydroxy-ethoxy)-propyl]-amide 251

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- hydroxy-phenyl)-ethyl]-amide 252

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(3- hydroxy-phenyl)-ethyl]-amide 253

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- hydroxy-cyclohexyl)-ethyl]-amide 254

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (trans-4- hydroxymethyl-cyclohexylmethyl)-amide 255

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (trans-4- hydroxymethyl- cyclohexylmethyl)-amide 256

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid {2-[2-(2- hydroxy-ethoxy)-ethoxy]-ethyl}-amide 257

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- fluoro-ethoxy)-ethyl]- amide258

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2,2- difluoro-ethoxy)-ethyl]-amide 259

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(2,2- difluoro-ethoxy)-ethyl]- amide 260

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- methoxy-ethoxy)-ethyl]-amide 261

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(2- methoxy-ethoxy)-ethyl]- amide 262

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- methoxy-ethoxy)-ethyl]-amide 263

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2- (tetrahydro-pyran-2-yl)-ethyl]-amide 264

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2- (tetrahydro-pyran-4-yl)-ethyl]-amide 265

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- cyano-ethoxy)-ethyl]- amide266

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(2- cyano-ethoxy)-ethyl]- amide 267

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- carbamoylmethoxy-ethyl)- amide268

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)- 1Hbenzoimidazole-5- carboxylic acid [2-(2- amino-ethoxy)-ethyl]- amide 269

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(2- amino-ethoxy)-ethyl]- amide 270

2-(4-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H benzoimidazole-5-carboxylic acid [2-(2- amino-ethoxy)-ethyl]- amide 271

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- methylamino-ethoxy)-ethyl]-amide hydrochloride 272

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(2- methylamino-ethoxy)- ethyl]-amide hydrochloride273

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- dimethylamino-ethoxy)-ethyl]-amide 274

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(2- dimethylamino-ethoxy)- ethyl]-amide 275

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- acetylamino-ethoxy)-ethyl]-amide 276

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- methanesulfonylamino-ethoxy)-ethyl]-amide 277

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2- ethanesulfonyl-ethyl)- amide 278

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(2- hydroxy-ethanesulfonyl)- ethyl]-amide 279

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(2- fluoro-ethylamino)-ethyl]- amide hydrochloride280

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((S)-2,3- dihydroxy-propyl)-amide281

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((R)-2,3- dihydroxy-propyl)-amide282

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((1R,2S,3R,4R)-2,3- dihydroxy-4-hydroxymethyl- cyclopentyl)-amide 283

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((2S,3R,4R,5S,6R)-2,4,5-trihydroxy-6- hydroxymethyl-tetrahydro- pyran-3-yl)-amide 284

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid bis-(2- hydroxy-ethyl)-amide 285

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (4- hydroxy-butyl)-amide 286

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- hydroxy-ethoxy)-ethyl]-amide 287

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (4- hydroxy-butyl)-amide 288

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(2- hydroxy-ethoxy)-ethyl]- amide 289

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid pyrrolidin- 3-ylamide hydrochloride290

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (R)- pyrrolidin-3-ylamide hydrochloride 291

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (S)- pyrrolidin-3-ylamide hydrochloride 292

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(R)-1-(2- hydroxy-ethyl)-pyrrolidin- 3-yl]-amide 293

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(S)-1-(2- hydroxy-ethyl)-pyrrolidin- 3-yl]-amide 294

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [1-((R)-2-hydroxy-propyl)-pyrrolidin- 3-yl]-amide 295

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(R)-1- ((S)-2-hydroxy-propionyl)-pyrrolidin-3-yl]-amide 296

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(R)-1- ((R)-2-hydroxy-propyl)- pyrrolidin-3-yl]-amide297

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [(R)-1- ((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]-amide 298

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [1-(2- hydroxy-2-methyl-propyl)-pyrrolidin-3-yl]-amide 299

3-(3-{[2-(6-Chloro- benzothiazol-2-ylamino)- 1-methyl-1H-benzoimidazole-5- carbonyl]-amino}- pyrrolidin-1-yl)-propionic acid 300

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [1-(2- methanesulfonylamino- ethyl)-pyrrolidin-3-yl]-amide 301

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2-methoxy- ethyl)-1H-benzoimidazole-5- carboxylic acid [1-(2- hydroxy-ethyl)-piperidin-4-yl]-amide 302

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (piperidin- 4-ylmethyl)-amide hydrochloride 303

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [1-(2- hydroxy-ethyl)-piperidin-4- ylmethyl]-amide 304

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2-methoxy- ethyl)-1H-benzoimidazole-5- carboxylic acid [1-(2- hydroxy-ethyl)-piperidin-4-ylmethyl]-amide 305

[4-(2-Hydroxy-ethyl)- piperazin-1-yl]-[1-methyl- 2-(6-trifluoromethoxy-benzothiazol-2-ylamino)- 1H-benzoimidazol-5-yl]- methanone 306

[2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H-benzoimidazol-5-yl]-[4-(2- hydroxy-ethyl)-piperazin- 1-yl]-methanone 307

[4-(3-Hydroxy-propyl)- piperidin-1-yl]-[1-methyl- 2-(6-trifluoromethoxy-benzothiazol-2-ylamino)- 1H benzoimidazol-5-yl]- methanone 308

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(R)-1-(2- dimethylamino-acetyl)- pyrrolidin-3-yl]-amide309

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (R)- piperidin-3-ylamide hydrochloride 310

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (S)- piperidin-3-ylamide hydrochloride 311

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(R)-1-(2- dimethylamino-acetyl)- piperidin-3-yl]-amide312

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(S)-1-(2- dimethylamino-acetyl)- piperidin-3-yl]-amide313

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [1-(2- dimethylamino-acetyl)- piperidin-4-yl]-amide 314

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [1-(2- dimethylamino-acetyl)- piperidin-4-ylmethyl]-amide 315

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2-methoxy- ethyl)-1H-benzoimidazole-5- carboxylic acid [1-(2- dimethylamino-acetyl)-piperidin-4-ylmethyl]- amide 316

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H benzoimidazole-5-carboxylic acid ((R)-1- methyl-pyrrolidin-3-yl)- amide 317

2-(6-Chloro-benzothiazol- 2 ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid ((S)-1- methyl-pyrrolidin-3-yl)- amide 318

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (1-methyl- piperidin-2-ylmethyl)- amide 319

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (1-methyl- piperidin-4-yl)-amide 320

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (1- methanesulfonyl- piperidin-4-yl)-amide 321

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid morpholin- 4-ylamide 322

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- methanesulfonylamino-ethyl)-amide 323

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- dimethylamino-acetylamino)-ethyl]-amide 324

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(2- dimethylamino- acetylamino)-ethyl]-amide 325

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- hydroxy-acetylamino)-ethyl]-amide 326

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((S)-2- hydroxy-propionylamino)-ethyl]-amide 327

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- imidazol-1-yl-ethyl)-amide 328

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2-pyrazol- 1-yl-ethyl)-amide 329

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2-oxo- pyrrolidin-1-yl)-ethyl]-amide 330

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2-oxo-imidazolidin-1-yl)-ethyl]- amide 331

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(3-oxo- piperazin-1-yl)-ethyl]- amide 332

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2-methoxy- ethyl)-1H-benzoimidazole-5- carboxylic acid [2-(3-oxo- piperazin-1-yl)-ethyl]-amide 333

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- piperidin-1-yl-ethyl)-amide 334

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2- piperidin-1-yl-ethyl)-amide 335

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(4,4- difluoro-piperidin-1-yl)- ethyl]-amide 336

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(3,3- difluoro-piperidin-1-yl)- ethyl]-amide 337

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- methyl-piperazin-1-yl)-ethyl]-amide 338

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(4- methyl-piperazin-1-yl)- ethyl]-amide 339

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2- piperazin-1-yl-ethyl)- amide hydrochloride 340

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2- morpholin-4-yl-ethyl)- amide 341

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- morpholin-4-yl-ethyl)- amide342

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(1,1- dioxo-thiomorpholin-4-yl)-ethyl]-amide 343

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2-amino- ethyl)-amide hydrochloride 344

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3-amino- propyl)-amidehydrochloride 345

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (3-amino- propyl)-amide hydrochloride 346

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (4-amino- butyl)-amidehydrochloride 347

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (4-amino- butyl)-amide hydrochloride 348

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3- dimethylamino-propyl)- amide349

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (3- dimethylamino-propyl)- amide 350

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3- dimethylamino-propyl)- amide351

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3- diethylamino-propyl)- amide 352

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (3- diethylamino-propyl)- amide 353

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3- diethylamino-propyl)- amide 354

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (3- pyrrolidin-1-yl-propyl)- amide 355

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [3-(4- methyl-piperazin-1-yl)-propyl]-amide 356

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [3-(4- methyl-piperazin-1-yl)- propyl]-amide 357

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [3-(4- methyl-piperazin-1-yl)-propyl]-amide 358

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3- morpholin-4-yl-propyl)- amide359

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (3- morpholin-4-yl-propyl)- amide 360

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (4- diethylamino-butyl)-amide 361

6-Diethylamino-1-methyl- 2-(6-trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid dimethylcarbamoylmethyl- amide 362

6-Diethylamino-1-methyl- 2-(6-trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- morpholin-4-yl-ethyl)- amide363

1-Methyl-2-(6-methyl- benzothiazol-2-ylamino)- 1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl- amide 364

2-(6-Ethoxy-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl- amide 365

2-(6-Isopropyl- benzothiazol-2-ylamino)- 1-methyl-1H- benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl- amide 366

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2-methoxy- ethyl)-1H-benzoimidazole-5- carboxylic acid dimethylcarbamoylmethyl- amide 367

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2- methylamino-ethyl)-1H-benzoimidazole-5- carboxylic acid dimethylcarbamoylmethyl- amidehydrochloride 368

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((S)-1- dimethylcarbamoyl-2-hydroxy-ethyl)-amide 369

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((S)-5- amino-1- dimethylcarbamoyl-pentyl)-amide hydrochloride 370

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((S)-5- dimethylamino-1-dimethylcarbamoyl- pentyl)-amide 371

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2- dimethylcarbamoyl-ethyl)- amide 372

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- dimethylcarbamoyl-ethyl)- amide373

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (3- morpholin-4-yl-3-oxo- propyl)-amide 374

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (3- morpholin-4-yl-3-oxo-propyl)-amide 375

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [3-(4- methyl-piperazin-1-yl)-3-oxo-propyl]-amide 376

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (3- dimethylcarbamoyl- propyl)-amide 377

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [4-(4- methyl-piperazin-1-yl)-4- oxo-butyl]-amide 378

4-{[2-(6-Chloro- benzothiazol-2-ylamino)- 1-methyl-1H- benzoimidazole-5-carbonyl]-amino}-trans- cyclohexanecarboxylic acid 379

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (4-trans- dimethylcarbamoyl- cyclohexyl)-amide 380

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid methylcarbamoylmethyl- amide 381

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid methylcarbamoylmethyl- amide 382

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [((R)-2- hydroxy- propylcarbamoyl)-methyl]- amide 383

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(2- methanesulfonyl- ethylcarbamoyl)-methyl]- amide 384

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(tetrahydro-furan-3- ylcarbamoyl)-methyl]- amide 385

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(tetrahydro-pyran-4- ylcarbamoyl)-methyl]- amide 386

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(1-methyl- piperidin-4-ylcarbamoyl)- methyl]-amide 387

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid ((R)- piperidin-3- ylcarbamoylmethyl)- amidehydrochloride 388

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [((R)-1- methyl-piperidin-3- ylcarbamoyl)-methyl]- amide389

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [(4- hydroxy- benzylcarbamoyl)-methyl]-amide 390

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid {[(2- hydroxy-ethyl)-methyl-carbamoyl]-methyl}-amide 391

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid {[(2- hydroxy-ethyl)-methyl- carbamoyl]-methyl}-amide392

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid {[bis-(2- hydroxy-ethyl)-carbamoyl]-methyl}-amide 393

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid {[methyl- (tetrahydro-pyran-4-yl)-carbamoyl]-methyl}-amide 394

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(methyl- pyrrolidin-3-yl-carbamoyl)- methyl]-amidehydrochloride 395

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid {[methyl- (1-methyl-pyrrolidin-3-yl)-carbamoyl]-methyl}-amide 396

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(methyl- piperidin-3-yl-carbamoyl)- methyl]-amidehydrochloride 397

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2-oxo-2- pyrrolidin-1-yl-ethyl)- amide 398

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(3- hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide 399

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(3- hydroxy-pyrrolidin-1-yl)-2- oxo-ethyl]-amide 400

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-((R)-3- hydroxy-pyrrolidin-1-yl)-2- oxo-ethyl]-amide401

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-((S)-3- hydroxy-pyrrolidin-1-yl)-2- oxo-ethyl]-amide402

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((R)-3-hydroxy-pyrrolidin-1-yl)-2- oxo-ethyl]-amide 403

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((S)-3-hydroxy-pyrrolidin-1-yl)-2- oxo-ethyl]-amide 404

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2-methoxy- ethyl)-1H-benzoimidazole-5- carboxylic acid [2-((R)-3- hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide 405

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2-methoxy- ethyl)-1H-benzoimidazole-5- carboxylic acid [2-((S)-3- hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide 406

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((S)-2-hydroxymethyl-pyrrolidin- 1-yl)-2-oxo-ethyl]-amide 407

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2- ((3S,4S)-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo- ethyl]-amide 408

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-((R)-3- methoxy-pyrrolidin-1-yl)- 2-oxo-ethyl]-amide409

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-((S)-3- methoxy-pyrrolidin-1-yl)- 2-oxo-ethyl]-amide410

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((S)-3-methoxy-pyrrolidin-1-yl)- 2-oxo-ethyl]-amide 411

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-((S)-3- amino-pyrrolidin-1-yl)-2- oxo-ethyl]-amidehydrochloride 412

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((S)-3-amino-pyrrolidin-1-yl)-2- oxo-ethyl]-amide hydrochloride 413

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((R)-3-methylamino-pyrrolidin-1- yl)-2-oxo-ethyl]-amide hydrochloride 414

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((S)-3-methylamino-pyrrolidin-1- yl)-2-oxo-ethyl]-amide hydrochloride 415

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((R)-3-dimethylamino-pyrrolidin- 1-yl)-2-oxo-ethyl]-amide 416

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((S)-3-dimethylamino-pyrrolidin- 1-yl)-2-oxo-ethyl]-amide 417

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-((R)-3- dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide 418

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-((S)-3- dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide 419

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-((S)-2- dimethylcarbamoyl- pyrrolidin-1-yl)-2-oxo-ethyl]-amide 420

3-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-3H-imidazo[4,5- b]pyridine-6-carboxylic acid (2-morpholin-4-yl-2-oxo-ethyl)-amide 421

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2- morpholin-4-yl-2-oxo- ethyl)-amide 422

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid (2- morpholin-4-yl-2-oxo-ethyl)-amide 423

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2-oxo-2- thiomorpholin-4-yl-ethyl)- amide 424

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(1,1- dioxo-thiomorpholin-4-yl)- 2-oxo-ethyl]-amide425

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid (2-oxo-2- piperazin-1-yl-ethyl)- amide hydrochloride 426

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(4- methyl-piperazin-1-yl)-2- oxo-ethyl]-amide 427

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- methyl-piperazin-1-yl)-2-oxo-ethyl]-amide 428

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2-methoxy- ethyl)-1H-benzoimidazole-5- carboxylic acid [2-(4- methyl-piperazin-1-yl)-2-oxo-ethyl]-amide 429

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(4- methanesulfonyl- piperazin-1-yl)-2-oxo-ethyl]-amide 430

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(4- dimethylsulfamoyl- piperazin-1-yl)-2-oxo-ethyl]-amide 431

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(3- hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide 432

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((R)-3-hydroxy-piperidin-1-yl)-2- oxo-ethyl]-amide 433

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-((S)-3- hydroxy-piperidin-1-yl)-2- oxo-ethyl]-amide434

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((S)-3-hydroxy-piperidin-1-yl)-2- oxo-ethyl]-amide 435

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide 436

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(4- hydroxy-piperidin-1-yl)-2- oxo-ethyl]-amide 437

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide 438

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2-methoxy- ethyl)-1H-benzoimidazole-5- carboxylic acid [2-(4- hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide 439

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(2- hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-amide 440

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(3- hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-amide 441

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-amide 442

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(4- hydroxymethyl-piperidin- 1-yl)-2-oxo-ethyl]-amide443

2-(6-Chloro-benzothiazol- 2-ylamino)-1-(2-methoxy- ethyl)-1H-benzoimidazole-5- carboxylic acid [2-(4- hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-amide 444

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-((S)-3- methoxy-piperidin-1-yl)-2- oxo-ethyl]-amide445

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((S)-3-methoxy-piperidin-1-yl)-2- oxo-ethyl]-amide 446

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-((R)-3-methoxy-piperidin-1-yl)-2- oxo-ethyl]-amide 447

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- methoxymethyl-piperidin-1-yl)-2-oxo-ethyl]-amide 448

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- fluoromethyl-piperidin-1-yl)-2-oxo-ethyl]-amide 449

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-oxo-2- (4-trifluoromethyl-piperidin-1-yl)-ethyl]- amide 450

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- cyano-piperidin-1-yl)-2-oxo-ethyl]-amide 451

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- carbamoyl-piperidin-1-yl)-2-oxo-ethyl]-amide 452

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid {2-oxo-2- [4-(pyrimidin-2-yloxy)-piperidin-1-yl]-ethyl}- amide 453

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- methylamino-piperidin-1-yl)-2-oxo-ethyl]-amide hydrochloride 454

2-(6-Chloro-benzothiazol- 2-ylamino-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(4- methylamino-piperidin-1- yl)-2-oxo-ethyl]-amidehydrochloride 455

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- dimethylamino-piperidin-1-yl)-2-oxo-ethyl]-amide 456

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(4- dimethylamino-piperidin- 1-yl)-2-oxo-ethyl]-amide457

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(4- methylaminomethyl- piperidin-1-yl)-2-oxo-ethyl]-amide hydrochloride 458

1-Methyl-2-(6- trifluoromethoxy- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [2-(4- dimethylaminomethyl-piperidin-1-yl)-2-oxo- ethyl]-amide 459

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(4- dimethylaminomethyl- piperidin-1-yl)-2-oxo-ethyl]-amide 460

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(3- methylaminomethyl- piperidin-1-yl)-2-oxo-ethyl]-amid hydrochloride 461

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [2-(3- dimethylaminomethyl- piperidin-1-yl)-2-oxo-ethyl]-amide 462

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid ((S)-1- dimethylcarbamoyl-ethyl)- amide 463

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((S)-1- dimethylcarbamoyl-ethyl)-amide 464

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(S)-1- methyl-2-(4-methyl- piperazin-1-yl)-2-oxo-ethyl]-amide 465

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid ((S)-1- methyl-2-morpholin-4-yl- 2-oxo-ethyl)-amide 466

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((S)-1- methyl-2-morpholin-4-yl-2-oxo-ethyl)-amide 467

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid ((R)-1- dimethylcarbamoyl-ethyl)- amide 468

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((R)-1- dimethylcarbamoyl-ethyl)-amide 469

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid [(R)-1- methyl-2-(4-methyl- piperazin-1-yl)-2-oxo-ethyl]-amide 470

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid [(R)-1- methyl-2-(4-methyl-piperazin-1-yl)-2-oxo- ethyl]-amide 471

2-(6-Chloro-benzothiazol- 2-ylamino)-1-methyl-1H- benzoimidazole-5-carboxylic acid ((R)-1- methyl-2-morpholin-4-yl- 2-oxo-ethyl)-amide 472

1-Methyl-2-(6- trifluoromethyl- benzothiazol-2-ylamino)-1H-benzoimidazole-5- carboxylic acid ((R)-1- methyl-2-morpholin-4-yl-2-oxo-ethyl)-amide

Compounds that increase levels or activity of HMOX1 are potentiallyuseful in treating diseases or conditions that may be associated atleast in part with oxidative stress such as, but not limited to,fibrotic diseases, neurodegenerative disease, cardiovascular disease,renal disease, inflammatory disease, liver disease, eye disease, thyroiddisease, viral infection, osteoporosis, pregnancy disorders,endometriosis, diabetes, and cancer. As used herein, the diseases orconditions associated with oxidative stress also include chronic effects(e.g., tissue damage, chronic inflammation) associated with persistentor long-term increases in oxidative stress due to the diseases orconditions described herein.

Fibrotic diseases associated with oxidative stress include, but are notlimited to, fibrotic diseases of the lung such as COPD, idiopathicpulmonary fibrosis, and sarcoidosis; fibrotic diseases of the liverincluding those caused by alcoholic cirrhosis, steatosis, cholestasis,drug side effect, and viral infection; and fibrotic diseases of the skinincluding autoimmune diseases such as scleroderma and psoriasis.

Neurodegenerative diseases associated with oxidative stress include, butare not limited to, Friedreich's ataxia, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis,and Charcot-Marie-Tooth syndrome.

Cardiovascular diseases associated with oxidative stress include, butare not limited to, hypertension, heart failure, hypercholesterolaemia,atherosclerosis, acute coronary thrombosis, deep vein thrombosis,peripheral vascular disease, congestive heart failure, acute coronarysyndrome, failure of arterial fistula for dialysis, and primarypulmonary hypertension.

Renal diseases associated with oxidative stress include, but are notlimited to, diabetic nephropathy, glomerular nephritis, and acutetubular necrosis.

Inflammatory diseases associated with oxidative stress include, but arenot limited to, asthma, chronic obstructive pulmonary disease,idiopathic pulmonary fibrosis, inflammatory bowel syndrome, Crohn'sdisease, celiac disease, scleroderma, systemic lupus erythematosus, andrheumatoid arthritis.

Liver diseases associated with oxidative stress include, but are notlimited to, drug induced liver toxicity, nonalcoholic steatohepatitis,and hepatitis C infection.

Eye diseases and conditions associated with oxidative stress include,but are not limited to, glaucoma, uveitis, wound healing (e.g., aftersurgery such as LASIK), eye trauma, corneal grafts, maculardegeneration, cataracts, light retinopathy, and retinopathy ofprematurity, as well as inflammation and tissue damage associated withthese diseases.

Thyroid diseases associated with oxidative stress include, but are notlimited to, Graves' disease, follicular adenoma, and papillary andfollicular carcinomas.

Viral infections associated with oxidative stress include both viralreplication of viruses, as well as tissue damage (e.g., fibrosis) due tooxidative stress resulting from chronic viral infection, for virusesincluding but are not limited to human immunodeficiency virus, hepatitisB, hepatitis C, and herpesvirus.

Diabetic conditions include, but are not limited to, type 1 diabetesmellitus, type 2 diabetes mellitus, gestational diabetes, pre-diabetes,hyperglycemia, and metabolic syndrome as well as secondary conditionsresulting from diabetic conditions (e.g., congestive heart failure andnephropathy).

The compounds of Formula (I) or pharmaceutically acceptable saltsthereof may therefore be useful in the treatment of one or more of thesediseases.

In one embodiment, the present invention provides a pharmaceuticalcomposition comprising the compound of Formula (I) or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a compound of any one of embodiments 1 to 271(recited above). In another embodiment, the pharmaceutical compositioncomprises a compound of any one of embodiments 1 to 271 and apharmaceutically acceptable carrier, excipient, diluent, or a mixturethereof.

In an embodiment, the pharmaceutical compositions containing a compoundof Formula (I) or a pharmaceutically acceptable salt thereof may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous, or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anyknown method, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents, and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxicpharmaceutically-acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example corn starch or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,356,108;4,166,452; and U.S. Pat. No. 4,265,874, to form osmotic therapeutictablets for controlled release.

In another embodiment, formulations for oral use may also be presentedas hard gelatin capsules where the active ingredient is mixed with aninert solid diluent, for example, calcium carbonate, calcium phosphateor kaolin, or a soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil.

In another embodiment, the composition may comprise an aqueoussuspension. Aqueous suspensions may contain the active compounds in anadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatidesuch as lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyl-eneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more coloring agents,one or more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Also, oily suspensions may be formulated by suspending the activeingredient in a vegetable oil, for example arachis oil, olive oil,sesame oil or coconut oil, or in a mineral oil such as a liquidparaffin. The oily suspensions may contain a thickening agent, forexample beeswax, hard paraffin or cetyl alcohol. Sweetening agents suchas those set forth above, and flavoring agents may be added to provide apalatable oral preparation. These compositions may be preserved by theaddition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, flavoring, and coloringagents may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oil, or a mineral oil, for example aliquid paraffin, or a mixture thereof. Suitable emulsifying agents maybe naturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening andflavoring agents.

In another embodiment, the pharmaceutical compositions of the presentinvention may comprise a syrup or elixir. Syrups and elixirs may beformulated with sweetening agents, for example glycerol, propyleneglycol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative and flavoring and coloring agents. Thepharmaceutical compositions may be in the form of a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known methods using suitable dispersing or wettingagents and suspending agents described above. The sterile injectablepreparation may also be a sterile injectable solution or suspension in anon-toxic parenterally-acceptable diluent or solvent, for example as asolution in 1,3-butanediol. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution, and isotonic sodiumchloride solution. In addition, sterile, fixed oils are convenientlyemployed as solvent or suspending medium. For this purpose, any blandfixed oil may be employed using synthetic mono- or diglycerides. Inaddition, fatty acids such as oleic acid find use in the preparation ofinjectables.

The pharmaceutical compositions of the present invention may also be inthe form of suppositories for rectal administration of the compounds ofthe invention. These compositions can be prepared by mixing the drugwith a suitable non-irritating excipient which is solid at ordinarytemperatures but liquid at the rectal temperature and will thus melt inthe rectum to release the drug. Such materials include cocoa butter andpolyethylene glycols, for example.

In an embodiment, for topical use, creams, ointments, jellies, solutionsof suspensions, etc., containing the compounds of the invention may beemployed. For the purpose of this application, topical applicationsshall include mouth washes and gargles.

In an embodiment, the compounds of Formula (I) and pharmaceuticallyacceptable salts thereof may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles, and multilamellar vesicles. Liposomes may beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Pharmaceutically-acceptable salts of compounds of Formula (I), where abasic or acidic group is present in the structure, are also includedwithin the scope of the invention. The term “pharmaceutically acceptablesalts” refers to salts of the compounds of this invention which are notbiologically or otherwise undesirable and are generally prepared byreacting the free base with a suitable organic or inorganic acid or byreacting the acid with a suitable organic or inorganic base.Representative salts include the following salts: Acetate,Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate,Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride, Clavulanate,Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate,Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate,Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride,Hydroxynaphthoate, Iodide, Isethionate, Lactate, Lactobionate, Laurate,Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate,Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate,N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate, Pantothenate,Phosphate/diphosphate, Polygalacturonate, Potassium, Salicylate, Sodium,Stearate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate,Triethiodide, Trimethylammonium and Valerate. When an acidic substituentis present, such as —COOH, there can be formed the ammonium,morpholinium, sodium, potassium, barium, calcium salt, and the like, foruse as the dosage form. When a basic group is present, such as amino ora basic heteroaryl radical, such as pyridyl, an acidic salt, such ashydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate,trichloroacetate, acetate, oxalate, maleate, pyruvate, malonate,succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate,methanesulfonate, ethanesulfonate, picrate and the like, and includeacids related to the pharmaceutically-acceptable salts recited inStephen M. Berge, et al., J. Pharm. Sci., Vol 66(1), pp. 1-19 (1977).

Thus, in another embodiment, the invention provides a pharmaceuticalcomposition comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarriers, excipients, or diluents. In another embodiment, the inventionprovides a pharmaceutical composition comprising a compound of any oneof embodiments 1 to 271 and one or more pharmaceutically acceptablecarriers, excipients, or diluents.

In another embodiment, the present invention provides a compound ofFormula (I) or a pharmaceutically acceptable salt thereof for use inmedicine. In another embodiment, the invention provides a compound ofany one of embodiments 1 to 271 for use in medicine.

The present invention further provides for the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, incombination with one or more medically effective active compounds forsimultaneous, subsequent, or sequential administration.

The invention also provides for the use of a compound of any one ofembodiments 1 to 271 in combination with one or more medically effectiveactive compounds for simultaneous, subsequent, or sequentialadministration. Examples of such medically effective active ingredientsinclude, but are not limited to, Nrf2 activators, antioxidants,detoxification agents, anti-inflammatory agents, and antidiabeticagents, e.g., metformin.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of any one of embodiments 1 to 271 and at leastone other medically effective active ingredient selected from Nrf2activators, antioxidants, detoxification agents, anti-inflammatoryagents, and antidiabetic agents, e.g., metformin. In another embodiment,the invention provides for the use of a compound of any one ofembodiments 1 to 271 in combination with at least one other medicallyeffective active ingredient selected from Nrf2 activators, antioxidants,detoxification agents, anti-inflammatory agents, and antidiabeticagents, e.g., metformin for simultaneous, subsequent, or sequentialadministration.

Examples of the Nrf2 activators include sulforaphane, avicins, 15dPGJ₂,xanthohumol, curcumin, carnosol, zerumbone, isothiocyanate, α-lipoicacid, oltipraz (4-methyl-5-[2-pyrazinyl]-1,2-dithiole-3-thione),1,2-dithiole-3-thione, and 2,3-butyl-4-hydroxyanisole.

Examples of the antioxidants include vitamin C, vitamin E, carotenoids,retinolds, polyphenols, flavonoids, lignan, selenium, butylatedhydroxyanisole, ethylene diamine tetra-acetate, calcium disodium,acetylcysteine, probucol, and tempo.

Examples of the detoxification agents include dimethyl caprol,glutathione, acetylcysteine, methionine, sodium hydrogen carbonate,deferoxamine mesylate, calcium disodium edetate, trientinehydrochloride, penicillamine, and pharmaceutical charcoal.

The anti-inflammatory agents include steroidal anti-inflammatory agentsand non-steroidal anti-inflammatory agents. Examples of the steroidalanti-inflammatory agents include cortisone acetate, hydrocortisone,paramethasone acetate, prednisolone, prednisolone, methylprednine,dexamethasone, triamcinolone, and betamethasone.

Examples of the non-steroidal anti-inflammatory agents include salicylicacid non-steroidal anti-inflammatory agents such as aspirin, difiunisal,aspirin+ascorbic acid, and aspirin dialuminate; aryl acid non-steroidalanti-inflammatory agents such as diclofenac sodium, sulindac, fenbufen,indomethacin, indomethacin farnesyl, acemetacin, proglumetacin maleate,anfenac sodium, nabmeton, mofezolac, and etodorag; fenamic acidnon-steroidal anti-inflammatory agents such as mefenamic acid,flufenamic acid aluminum, tolfenamic acid, and floctafenine; propionicacid non-steroidal anti-inflammatory agents such as ibuprofen,flurbiprofen, ketoprofen, naproxen, pranoprofen, fenoprofen calcium,thiaprofen, oxaprozin, loxoprofen sodium, alminoprofen, and zaltoprofen;oxicam non-steroldal anti-inflammatory agents such as piroxicam,ampiroxicam, tenoxicam, lornoxicam, and meloxicam; and basicnon-steroidal anti-inflammatory agents such as tiaramide hydrochloride,epirizole, and emorfazone.

Methods of Use

A compound of Formula (I) or pharmaceutically acceptable salt thereof,or a pharmaceutical composition comprising a compound of Formula (I) orpharmaceutically acceptable salt thereof may be used for the treatmentof a disease or condition which is treatable by activation oftranscription factor Nrf2, by increasing the activity and/or the amountof HMOX1, or by reducing amounts of ROS in a subject. The treatment canbe systemic or targeted, for example targeted to an inducibleheme-oxygenase found in monocytes and macrophages in the human body.

Examples of a disease or condition which may be treatable by activationof transcription factor Nrf2, by increasing the activity and/or theamount of HMOX1, or by reducing amounts of ROS in a subject, includecerebral nerve degenerative diseases, eye diseases, skin diseases,asthma, cancer, arteriosclerosis and diseases or conditions relatedthereto. Examples of the cerebral nerve degenerative diseases includeAlzheimer's disease, Parkinson's disease, and amyotrophic lateralsclerosis. Further, examples of the eye diseases include age-relatedmacular degeneration, cataracts, light retinopathy, and retinopathy ofprematurity. Specific examples of the chronic inflammatory diseasesinclude vasculitis, pulmonary bronchitis, rheumatoid arthritis,osteoarthritis, hepatitis, pancreatitis, dermatitis, esophagitis,ulcerative colitis, Crohn's disease, and conjunctivitis. Furtherexamples of conditions that may be treatable include thrombosis anddiseases of the kidney.

Examples of a disease or condition which may be treatable by activationof transcription factor Nrf2, by increasing the activity and/or theamount of HMOX1, or by reducing amounts of ROS in a subject, include,but are not limited to, fibrotic diseases, neurodegenerative disease,cardiovascular disease, renal disease, inflammatory disease, liverdisease, eye disease, thyroid disease, viral infection, osteoporosis,pregnancy disorders, endometriosis, diabetes, and cancer. As usedherein, the diseases or conditions associated with oxidative stress alsoinclude chronic effects (e.g., tissue damage, chronic inflammation)associated with persistent or long-term increases in oxidative stressdue to the diseases or conditions described herein.

Fibrotic diseases associated with oxidative stress include, but are notlimited to, fibrotic diseases of the lung such as COPD, idiopathicpulmonary fibrosis, and sarcoidosis; fibrotic diseases of the liverincluding those caused by alcoholic cirrhosis, steatosis, cholestasis,drug side effect, and viral infection; and fibrotic diseases of the skinincluding autoimmune diseases such as scleroderma and psoriasis.

Neurodegenerative diseases associated with oxidative stress include, butare not limited to, Friedreich's ataxia, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis,and Charcot-Marie-Tooth syndrome.

Cardiovascular diseases associated with oxidative stress include, butare not limited to, hypertension, heart failure, hypercholesterolaemia,atherosclerosis, acute coronary thrombosis, deep vein thrombosis,peripheral vascular disease, congestive heart failure, acute coronarysyndrome, failure of arterial fistula for dialysis, and primarypulmonary hypertension.

Renal diseases associated with oxidative stress include, but are notlimited to, diabetic nephropathy, glomerular nephritis, and acutetubular necrosis.

Inflammatory diseases associated with oxidative stress include, but arenot limited to, asthma, chronic obstructive pulmonary disease,idiopathic pulmonary fibrosis, inflammatory bowel syndrome, Crohn'sdisease, celiac disease, scleroderma, systemic lupus erythematosus, andrheumatoid arthritis.

Liver diseases associated with oxidative stress include, but are notlimited to, drug induced liver toxicity, nonalcoholic steatohepatitis,and hepatitis C infection.

Eye diseases and conditions associated with oxidative stress include,but are not limited to, glaucoma, uveitis, wound healing (e.g., aftersurgery such as LASIK), eye trauma, corneal grafts, maculardegeneration, cataracts, light retinopathy, and retinopathy ofprematurity, as well as inflammation and tissue damage associated withthese diseases.

Thyroid diseases associated with oxidative stress include, but are notlimited to, Graves' disease, follicular adenoma, and papillary andfollicular carcinomas.

Viral infections associated with oxidative stress include both viralreplication of viruses, as well as tissue damage (e.g., fibrosis) due tooxidative stress resulting from chronic viral infection, for virusesincluding but are not limited to human immunodeficiency virus, hepatitisB, hepatitis C, and herpesvirus.

Diabetic conditions include, but are not limited to, type 1 diabetesmellitus, type 2 diabetes mellitus, gestational diabetes, pre-diabetes,hyperglycemia, and metabolic syndrome as well as secondary conditionsresulting from diabetic conditions (e.g., congestive heart failure andnephropathy).

Thus the present invention provides a method of treatment comprisingadministering to a subject a compound of Formula (I) or apharmaceutically acceptable salt thereof so as to treat at least one ofthe diseases or conditions listed above.

In one embodiment, the invention provides a method of treatmentcomprising administering a compound of any one of embodiments 1 to 271to a human. In another embodiment, the invention provides a method oftreatment comprising administering at least 0.1 milligrams of a compoundof any one of embodiments 1 to 271 to a human.

In another embodiment, the invention provides a method of treatmentcomprising administering a compound of any one of embodiments 1 to 271to a human, so as to treat chronic inflammation. In a furtherembodiment, the invention provides a method of treatment comprisingadministering a compound of any one of embodiments 1 to 271 to a human,so as to treat a disease or condition selected from rheumatoidarthritis, a chronic inflammatory bowel disease, multiple sclerosis,asthma, airways inflammatory disease, tendonitis, and chronicinflammation in the brain.

In another embodiment, the invention provides a compound of any one ofembodiments 1 to 271 for use in medicine. In another embodiment, theinvention provides a compound of any one of embodiments 1 to 271 for usein the treatment of chronic inflammation. In another embodiment, theinvention provides a compound of any one of embodiments 1 to 271 for usein the prevention of chronic inflammation. In another embodiment, theinvention provides a compound of any one of embodiments 1 to 271 for usein the treatment of a disease or condition selected from rheumatoidarthritis, a chronic inflammatory bowel disease, multiple sclerosis,asthma, airways inflammatory disease, tendonitis, and chronicinflammation in the brain. In another embodiment, the invention providesa compound of any one of embodiments 1 to 271 for use in the preventionof a disease or condition selected from rheumatoid arthritis, a chronicinflammatory bowel disease, multiple sclerosis, asthma, airwaysinflammatory disease, tendonitis, and chronic inflammation in the brain.

In another embodiment, the invention provides the use of a compound ofany one of embodiments 1 to 271 for the preparation of a medicament forthe treatment of chronic inflammation. In another embodiment, theinvention provides the use of a compound of any one of embodiments 1 to271 for the preparation of a medicament for the prevention of chronicinflammation. In another embodiment, the invention provides the use of acompound of any one of embodiments 1 to 271 for the preparation of amedicament for the treatment of a disease or condition selected fromrheumatoid arthritis, a chronic inflammatory bowel disease, multiplesclerosis, asthma, airways inflammatory disease, tendonitis, and chronicinflammation in the brain. In a further embodiment, the inventionprovides the use of a compound of any one of embodiments 1 to 271 forthe preparation of a medicament for the prevention of a disease orcondition selected from rheumatoid arthritis, a chronic inflammatorybowel disease, multiple sclerosis, asthma, airways inflammatory disease,tendonitis, and chronic inflammation in the brain. In anotherembodiment, the invention provides the use of a compound of any one ofembodiments 1 to 271 for the preparation of a medicament for theprevention of a disease or condition selected from rheumatoid arthritis,a chronic inflammatory bowel disease, multiple sclerosis, asthma,airways inflammatory disease, tendonitis, and chronic inflammation inthe brain. In a further embodiment, the invention provides the use of acompound of any one of embodiments 1 to 271 for the preparation of amedicament for the prevention of a disease or condition selected fromrheumatoid arthritis, a chronic inflammatory bowel disease, multiplesclerosis, asthma, airways inflammatory disease, tendonitis, and chronicinflammation in the brain.

In another embodiment, the invention provides a method of treatmentcomprising administering to a human a compound of any one of embodiments1 to 271 so as to increase the activity or amount of HMOX1 in a subject.In a further embodiment, the invention provides for the use of acompound of any one of embodiments 1 to 271 for the preparation of amedicament for increasing the activity or amount of HMOX1 in a human.

In another embodiment, the invention provides a method of treatmentcomprising administering a compound of any one of embodiments 1 to 271to a human, so as to treat a disease or condition selected from:cardiovascular disease including arteriosclerosis, peripheral vasculardisease, thrombosis, ischemia-reperfusion events, congestive heartfailure, primary and secondary pulmonary arterial hypertension andhypertension; renal diseases such as acute tubular necrosis;glomerulonephritis, including diabetic related complications includingglomerular nephropathy and supportive care for dialysis includingmaintenance of arterial fistulas; pulmonary diseases includingbronchitis, bronchiecstasis, chronic obstructive pulmonary disease,pulmonary edema, asthma, emphysema, sarcoidosis; liver disease includingthose leading to scarring and fibrosis such as cholestasis, hepatitis Band C infection, cirrhosis; autoimmune diseases and their complicationsincluding rheumatoid arthritis, ankylosing spondylosis, systemic lupuserthyamatosus, scleroderma and psoriasis; cerebral nerve degenerativediseases including Alzheimers disease, Parkinsons disease, ALS(amyotrophic lateral sclerosis) and multiple sclerosis; skin diseases;eye diseases including macular degeneration, cataracts, lightretinopathy, and retinopathy of diabetes, prematurity; and cancer;supportive care for transplantation including graft viability andreduction of ischemic damage.

In another embodiment, the invention provides a compound of any one ofembodiments 1 to 271 for use in the treatment of a disease or conditionselected from: cardiovascular disease including arteriosclerosis,peripheral vascular disease, thrombosis, ischemia-reperfusion events,congestive heart failure, primary and secondary pulmonary arterialhypertension and hypertension; renal diseases such as acute tubularnecrosis; glomerulonephritis, including diabetic related complicationsincluding glomerular nephropathy and supportive care for dialysisincluding maintenance of arterial fistulas; pulmonary diseases includingbronchitis, bronchiecstasis, chronic obstructive pulmonary disease,pulmonary edema, asthma, emphysema, sarcoidosis; liver disease includingthose leading to scarring and fibrosis such as cholestasis, hepatitis Band C infection, cirrhosis; autoimmune diseases and their complicationsincluding rheumatoid arthritis, ankylosing spondylosis, systemic lupuserthyamatosus, scleroderma and psoriasis; cerebral nerve degenerativediseases including Alzheimers disease, Parkinsons disease, ALS(amyotrophic lateral sclerosis) and multiple sclerosis; skin diseases;eye diseases including macular degeneration, cataracts, lightretinopathy, and retinopathy of diabetes, prematurity; and cancer;supportive care for transplantation including graft viability andreduction of ischemic damage.

In another embodiment, the invention provides a compound of any one ofembodiments 1 to 271 for use in the prevention of a disease or conditionselected from: cardiovascular disease including arteriosclerosis,peripheral vascular disease, thrombosis, ischemia-reperfusion events,congestive heart failure, primary and secondary pulmonary arterialhypertension and hypertension; renal diseases such as acute tubularnecrosis; glomerulonephritis, including diabetic related complicationsincluding glomerular nephropathy and supportive care for dialysisincluding maintenance of arterial fistulas; pulmonary diseases includingbronchitis, bronchiecstasis, chronic obstructive pulmonary disease,pulmonary edema, asthma, emphysema, sarcoidosis; liver disease includingthose leading to scarring and fibrosis such as cholestasis, hepatitis Band C infection, cirrhosis; autoimmune diseases and their complicationsincluding rheumatoid arthritis, ankylosing spondylosis, systemic lupuserthyamatosus, scleroderma and psoriasis; cerebral nerve degenerativediseases including Alzheimers disease, Parkinsons disease, ALS(amyotrophic lateral sclerosis) and multiple sclerosis; skin diseases;eye diseases including macular degeneration, cataracts, lightretinopathy, and retinopathy of diabetes, prematurity; and cancer;supportive care for transplantation including graft viability andreduction of ischemic damage.

In another embodiment, the invention provides for the use of a compoundof any one of embodiments 1 to 271 for the preparation of a medicamentfor the treatment of a disease or condition selected from:cardiovascular disease including arteriosclerosis, peripheral vasculardisease, thrombosis, ischemia-reperfusion events, congestive heartfailure, primary and secondary pulmonary arterial hypertension andhypertension; renal diseases such as acute tubular necrosis;glomerulonephritis, including diabetic related complications includingglomerular nephropathy and supportive care for dialysis includingmaintenance of arterial fistulas; pulmonary diseases includingbronchitis, bronchiecstasis, chronic obstructive pulmonary disease,pulmonary edema, asthma, emphysema, sarcoidosis; liver disease includingthose leading to scarring and fibrosis such as cholestasis, hepatitis Band C infection, cirrhosis; autoimmune diseases and their complicationsincluding rheumatoid arthritis, ankylosing spondylosis, systemic lupuserthyamatosus, scleroderma and psoriasis; cerebral nerve degenerativediseases including Alzheimers disease, Parkinsons disease, ALS(amyotrophic lateral sclerosis) and multiple sclerosis; skin diseases;eye diseases including macular degeneration, cataracts, lightretinopathy, and retinopathy of diabetes, prematurity; and cancer;supportive care for transplantation including graft viability andreduction of ischemic damage.

In another embodiment, the invention provides for the use of a compoundof any one of embodiments 1 to 271 for the preparation of a medicamentfor the prevention of a disease or condition selected from:cardiovascular disease including arteriosclerosis, peripheral vasculardisease, thrombosis, ischemia-reperfusion events, congestive heartfailure, primary and secondary pulmonary arterial hypertension andhypertension; renal diseases such as acute tubular necrosis;glomerulonephritis, including diabetic related complications includingglomerular nephropathy and supportive care for dialysis includingmaintenance of arterial fistulas; pulmonary diseases includingbronchitis, bronchiecstasis, chronic obstructive pulmonary disease,pulmonary edema, asthma, emphysema, sarcoidosis; liver disease includingthose leading to scarring and fibrosis such as cholestasis, hepatitis Band C infection, cirrhosis; autoimmune diseases and their complicationsincluding rheumatoid arthritis, ankylosing spondylosis, systemic lupuserthyamatosus, scleroderma and psoriasis; cerebral nerve degenerativediseases including Alzheimers disease, Parkinsons disease, ALS(amyotrophic lateral sclerosis) and multiple sclerosis; skin diseases;eye diseases including macular degeneration, cataracts, lightretinopathy, and retinopathy of diabetes, prematurity; and cancer;supportive care for transplantation including graft viability andreduction of ischemic damage.

In each of the methods or uses described above, a compound of any ofembodiments 1 to 271 may be administered to a subject as part of apharmaceutically formulation, as described above.

EXAMPLES

The general procedures used in the methods to prepare the compounds ofthe present invention are described below.

General Experimental Section

LC-MS data are obtained using gradient elution on a parallel MUX™system, running four Waters® 1525 binary HPLC pumps, equipped with aMux-UV 2488 multichannel UV-Vis detector (recording at 215 and 254 nM)and a Leap Technologies HTS PAL Auto sampler using a Sepax GP-C18,4.6×50 mm; 5 micron particle-size column. In general, a three minutegradient is run from 25% B (97.5% acetonitrile, 2.5% water, 0.05% TFA)and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B. Thesystem is interfaced with a Waters Micromass ZQ mass spectrometer usingelectrospray ionization. MassLynx software is employed. All MS data wereobtained in the positive mode unless otherwise noted. The reported m/zdata are generally accurate within about ±1 for the M+ ion.

¹H NMR data were obtained on a Varian® Mercury 400 MHz spectrometer andchemical shifts were referenced using either the residual solvent protonsignal (e.g., residual CHCl₃ in CDCl₃) or the TMS signal as an internalreference. Microwave heating procedures were used in some experimentsand, in these cases, a Discover® microwave synthesis system (CEM,Matthews, N.C., USA) was used which included the use of pressurizedglass reaction vessels at elevated temperatures.

All reagents and solvents including anhydrous solvents were commerciallyavailable and were used as received unless described otherwise. Anysolutions of Grignard reagents and organolithium reagents werecommercially available and were used as received and at theconcentrations listed on their labels. Reactions are stirred using amagnetic stirring apparatus and magnetic stir bar in most cases. Allreactions using air-sensitive reagents were run under inert gas. Forreactions not heated using a microwave-generating apparatus, thereaction temperatures reported in the experimental section refer to thetemperatures of an oil bath or cooling bath placed around a reactionvessel. For reactions performed using a microwave-generating apparatus,the temperatures refer to the temperatures reported by the microwaveapparatus.

Abbreviations

Below are definitions of some common abbreviations that are used in thespecification. The specification may also employ other abbreviationswhose meanings are well known in the relevant art.

-   AcOH=acetic acid-   DCM=dichloromethane-   DIEA=diisopropylethylamine-   DMAP=N,N′-dimethylamino pyridine-   DME=1,2-dimethoxyethane-   DMF=N,N′-dimethylformamide-   DMSO=dimethylsulfoxide-   DPPA=diphenylphosphoryl azide-   EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-   EtOAc=ethyl acetate-   EtOH=ethanol-   ¹H NMR=proton NMR analysis-   HBTU=2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HCl=hydrochloric acid-   LC/MS=liquid chromatography-mass spectrometry analysis-   MeOH=methanol-   OAc=acetate-   THF=tetrahydrofuran-   thioCDI=1,1′-thiocarbonyldiimidazole-   TLC=thin layer chromatography-   rt or RT=room temperature-   h=hour-   min=minutes-   M=molar concentration-   N=normal concentration-   uL=ul=microliters-   mL=ml=milliliters-   ug=micrograms-   mg=milligrams-   g=grams    General Procedure A: Ipso Substitution of o- or p-Nitrohaloarene

To a DMF solution of a nitrohaloarene would be added an amine or sodiumalkoxide, and the reaction mixture would be stirred at room temperaturefor 16 h. It would be poured into water and extracted with ethylacetate. The combined organic extracts would be washed with water,washed with brine, dried over sodium sulfate, filtered, and concentratedunder vacuum to give the product, which would not be purified furtherand would be used directly in the next step.

General Procedure B: Reduction of Nitro Group to Amine

10% Pd/C would be added to a solution of the nitro compound in methanol.The resulting mixture would be stirred at room temperature under a H₂atmosphere for 16 h. The contents would then be filtered through a padof Celite or silica gel and the solid would be washed with portions ofmethanol. The filtrate and washings would be combined and evaporated toafford the corresponding amine, which would not be purified further andused directly in the next step.

General Procedure C: Formation of Aminobenzothiazoles

To a suspension of the aniline in acetic acid would be added potassiumisothiocyanate and the reaction mixture was allowed to stir at roomtemperature for 10 min. A solution of bromine (1.5 mL in acetic acid (20mL) would then be added over 20 min. The reaction mixture would bestirred at room temperature for 24 h then poured onto ice-cold water,made alkaline with 28% aqueous ammonium hydroxide and the resultingprecipitate would be filtered, washed with water, and dried underreduced pressure to give the desired substituted aminobenzothiazoles.The product would be used in the next step without further purification.

General Procedure D: Thiourea Formation and its Conversion toAminobenzimidazole

1,1′-Thiocarbonylimidazole would be added to a solution of amine in DMF(10 mL) and the reaction mixture would be stirred at 90-100° C. (1-24h). To this reaction mixture at room temperature would be added EDC andstirred at 60° C. for 5 min. To this reaction mixture at roomtemperature would be added substituted phenylenediamine and would bestirred at 90° C. for 16 h. The reaction mixture would then be cooled toroom temperature, poured into ice-cold water and the solid would becollected by filtration. The crude product thus obtained would bepurified by trituration with DCM-methanol (9:1).

General Procedure E: Hydrolysis of Benzoate Ester

A solution of LiOH in water would be added to a solution of ester in 1:1THF/MeOH and the resulting mixture would be stirred at 60° C. for 16 h.After completion of the reaction, the mixture would be concentratedunder vacuum. The pH of the resulting suspension would be adjusted bythe dropwise addition of 6 N HCl to pH ˜3 and the precipitate would becollected by filtration, washed with water and dried under vacuum. Thedesired carboxylic acid would be used without purification.

General Procedure F: Amide Formation Using HBTU as Coupling Reagent

To a solution of a carboxylic acid in dry DMF (5-10 mL) would be addedDIEA followed by HBTU and the reaction mixture was stirred at roomtemperature for 30 min. An amine would then be added, and the reactionwould be stirred at room temperature for 16 h. The contents would bediluted with ice-water and the product would be precipitated. The pureproduct would be isolated after filtration either with subsequentwashings with water and DCM/Methanol or through silica gelchromatography using hexanes/ethyl acetate (from 80:20 to 60:40) as anluent system.

General Procedure G: Alkylnitrile Reduction

Lithium aluminum hydride would be suspended in dry ether (50 mL) andcooled to 0° C. under a nitrogen atmosphere. The nitrile in dry ether(12.5 mL) would be added dropwise, and the reaction mixture would bestirred overnight at room temperature. With cooling and vigorousstirring, water (3 mL), sodium hydroxide (20%, 3 mL), and water (10 mL)would be added. The ether solution would be decanted and the residuewould be washed with ether (2×12.5 mL). The ether portions would becombined, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo.

General Procedure H: Fluorination of an Alcohol

To a DCM suspension of the alcohol, cooled to 0° C., would be addedbis(2-methoxyethyl)aminosulfur trifluoride dropwise. The reaction wouldbe allowed to return to room temperature and stirred for 6 h. It wouldthen be cooled to 0° C., and water (3 mL) would be added dropwise. Theaqueous phase would be extracted with DCM (2×3 mL). The combinedorganics would be dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo.

General Procedure I: Imidazole Formation

Step 1: The arylnitrile (product which was obtained following thegeneral procedure D) would be dissolved in absolute ethanol (25 mL) andto this solution hydrochloric acid gas would carefully be cannulated at−10° C. within 30 min. The reaction mixture would be sealed and stirredat room temperature for 16 h to give aryl ethylimidate. This crudeproduct would then be used in next step without further purification.

Step 2: To a solution of aryl ethylimidate in EtOH (10 mL) would beadded aminoacetaldehyde diethylacetal and AcOH. This mixture would thenbe heated to 60° C. and stirred for 2 h. The reaction mixture would thenbe cooled down and concentrated under vacuum. This crude material wouldagain be dissolved in EtOH (10 ml) and hydrochloric acid (0.2 mL, 6N inwater) added to the mixture and refluxed at 85° C. for 16 h. Aftercompletion of the reaction, the mixture would then be concentrated undervacuum and basified with triethylamine and purified with silica gelchromatography using DCM:MeOH (95:5 to 80:20) to give desiredimidazoles. (53-76% yields).

General Procedure J: Triazole Formation

Method A: To a solution of benzamide in toluene (10 mL) would be addedN,N-dimethylformamide diethylacetal and heated to 110° C. and refluxedfor 3 h. The reaction mixture would then be cooled down and concentratedunder vacuum. This residue would then be dissolved in AcOH (2 mL) andhydrazine (1.0 M solution in THF) was added, and the solution would beheated to 100° C. and stirred at this temperature for 4 h. Aftercompletion of the reaction, the mixture would be concentrated and pouredinto cold saturated sodium bicarbonate solution (25 mL) and extractedwith ethyl acetate (2×25 mL). The combined organic extracts would bewashed with water (25 mL) and brine (25 mL), dried over sodium sulfate,and concentrated under vacuum. This residue would then be purified withsilica gel chromatography using DCM:ethyl acetate (70:30 to 50:50) as aneluent system to give the desired triazoles (58-66% yields).

Method B: To a solution of aryl ethylimidate in EtOH (10 mL) would beadded formic or acetic hydrazide. The reaction mixture would then berefluxed for 4 h. The mixture would be concentrated under vacuum andpurified with silica gel chromatography using DCM:ethyl acetate (70:30to 40:60) to give desired triazoles (47-61% yields).

General Procedure K: Methyl Ester Formation

To a methanol solution of the benzoic acid cooled to 0° C. using an icebath, would be added thionyl chloride dropwise. The reaction mixturewould then be heated at 50° C. for 5 h. The solvent would be evaporated,and ethyl acetate and saturated aqueous sodium bicarbonate would beadded. The phases would be separated, and the aqueous phase would beextracted twice with ethyl acetate. The combined organics would be driedover sodium sulfate and then filtered. The solvent would be evaporatedto give the pure methyl ester.

General Procedure L: Removal of t-Boc Group to Give Arylamines

A solution of aryl amino-tert-butylester in DCM (10 mL) would be addedto hydrochloric acid (3 eq., and 4.0 N solution in dioxane) at roomtemperature and stirred for 3 h. After completion of the reaction, themixture would be concentrated under vacuum and the residue would bewashed with ether (10 ml) to remove unwanted organic impurities, andthen triturated with DCM:hexanes (2:8) to give the desired amines ashydrochloric acid salts (77-85% yields).

General Procedure M: Formation of Alkylsulfones from Alkylsulfides

A solution of alkylsulfide in DCM would be added peracetic acid (2 eq.,32 wt % solution in acetic acid) at −10° C. Then the reaction mixturewould be stirred at room temperature for 2-6 h. After completion of thereaction, the mixture would be poured into saturated sodium bicarbonatesolution (25 mL) and extracted with DCM (25 mL), dried over sodiumsulfate and concentrated under vacuum. The residue would then betriturated with DCM:hexanes (2:8) to give the desired sulfones. Ifnecessary, the residue would be purified with silica gel chromatographyusing DCM:ethyl acetate (80:20 to 60:40) as eluent system to provide thedesired sulfones (88-96% yields).

General Procedure N: Amide Formation Using DPPA as Coupling Reagent

To a solution of a carboxylic acid in dry DMF would be added DIEAfollowed by DPPA and the reaction mixture would be stirred at roomtemperature for 30 min. The amine would then be added, and the reactionwould be stirred at room temperature for 2 h. The contents would bediluted with ice-water and the product would be precipitated. The pureproduct would be isolated after filtration either with subsequentwashings with water and DCM/Methanol or through silica gelchromatography using hexanes/ethyl acetate as eluent.

General Procedure O: Fmoc Deprotection

To a DMF solution of fluroenylmethyl carbamate of an amine at roomtemperature would be added 20% (v/v) piperidine. The reaction mixturewould then be stirred for 2 h. The reaction mixture would be added toethyl acetate and saturated aqueous sodium bicarbonate. The phases wouldbe separated, and the aqueous phase would be extracted twice with ethylacetate. The combined organics would be dried over sodium sulfate andthen filtered. The solvent would be evaporated and crude compound wouldbe purified by flash chromatography using DCM:methanol as eluent.

General Procedure P: Reductive Amination

To a DCM solution of amine at room temperature would be added aldehydeand sodium triacetoxyborohydride. The reaction mixture would then bestirred for 2-8 h. The reaction would be added to DCM and saturatedaqueous sodium bicarbonate. The phases would be separated, and theaqueous phase would be extracted twice with DCM. The combined organicswould be dried over sodium sulfate and then filtered. The solvent wouldbe evaporated and crude compound would be purified by flashchromatography using DCM:methanol as eluent.

General Procedure Q: Sulfonamide Formation

To a DCM solution of amine at 0° C. would be added triethylaminefollowed by dropwise addition of sulfonyl chloride. The reaction mixturewould then be stirred at 0° C. for 20 min and then at room temperaturefor 30 min. The reaction would be added to DCM and saturated aqueoussodium bicarbonate. The phases would be separated, and the aqueous phasewould be extracted twice with DCM. The combined organics would be driedover sodium sulfate and then filtered. The solvent would be evaporatedand crude compound would be purified by flash chromatography usingDCM:methanol as eluent.

General Procedure R: Amide Formation

To a DCM solution of amine at 0° C. would be added triethylaminefollowed by dropwise addition of acyl chloride. The reaction mixturewould then be stirred at 0° C. for 20 min and then at room temperaturefor 30 min. The reaction would be added to DCM and saturated aqueoussodium bicarbonate. The phases would be separated, and the aqueous phasewould be extracted twice with DCM. The combined organics would be driedover sodium sulfate and then filtered. The solvent would be evaporatedand crude compound would be purified by flash chromatography usingDCM:methanol as eluent.

General Procedure S: Alkylation of Alcohol/Amine

To a dioxane or DMF solution of alcohol/amine at room temperature wouldbe added dibenzyl-(2-chloro-ethyl)-amine followed by 50% (w/w) aqueousKOH solution or DIEA and catalytic amount of tetrabutylammonium bromide.The reaction mixture would be stirred at 55° C. for 8 h. The reactionwould be added to saturated sodium chloride solution and extracted withethyl acetate. The phases would be separated, and the combined organicswould be dried over sodium sulfate and then filtered. The solvent wouldbe evaporated and crude compound would be purified by flashchromatography using hexane:ethyl acetate as eluent.

General Procedure T: Debenzylation of Amine

To a methanol solution of dibenzyl amine at room temperature would beadded Pd—C 20% by weight. The reaction mixture would be subjected tohydrogen atmosphere at 60 PSI at room temperature for 12-24 h. Thereaction mixture would be filtered through celite and washed withmethanol. The filtrate would be evaporated to isolate pure compound.

General Procedure U: Conversion of Alkyl Halide to Azide

To a solution of alkyl bromide in dry DMF would be added sodium azide,and the reaction mixture would be stirred at room temperature for 16 h.After completion of the reaction, the contents would be diluted withethyl acetate and washed with water, dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo.

General Procedure V: Conversion of Alcohol to Tosylate

To a solution of alcohol in pyridine would be added DMAP, and thereaction mixture would be cooled to 0° C. p-Toluenesulfonyl chloridewould be added, and the reaction mixture would continue to stir at 0° C.for 3 h. After completion of the reaction, the contents would be dilutedwith ethyl acetate and washed with 1 N HCl, with saturated aqueoussodium bicarbonate, and then with water. It would then be dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo.

General Procedure W: Reaction of Tosylate and Alcohol

To a solution of alcohol and tosylate in toluene would be added a 50%aqueous NaOH solution and tetrabutylammonium hydrogen sulfate. Thereaction mixture would be stirred at 80° C. for 3 h then stirred at 50°C. for 16 h. After completion of the reaction, an aqueous ammoniumchloride solution would be added, and the reaction mixture would befurther diluted with ethyl acetate. The phases would be separated, andthe aqueous phase would be extracted with ethyl acetate. The combinedorganic phases would be dried over anhydrous sodium sulfate, filtered,and concentrated in vacuo.

General Procedure X: Epoxide Opening with an Alcohol

To a solution of alcohol and epoxide in dry DMF would be added potassiumhydroxide, and the reaction mixture would be stirred at room temperaturefor 16 h then at 60° C. for another 24 h. After completion of thereaction, the contents would be concentrated in vacuo. The pure productwould be isolated through silica gel chromatography.

Example 11-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl amide

4-Methylamino-3-nitro-benzoic acid (825 mg) was prepared by followingGeneral Procedure A starting from 4-fluoro-3-nitro-benzoic acid (1.0 g)and methylamine (2 M in THF, 8.1 mL) in THF. The crude product was usedin the next step without further purification.

Synthesis of N-methyl-4-methylamino-3-nitro-benzamide (375 mg) wasprepared by following General Procedure F starting from4-methylamino-3-nitro-benzoic acid (500 mg), HBTU (1.45 g), DIEA (0.89mL), and methylamine (2 M in THF, 8.1 mL). Purification was carried outusing silica gel chromatography using hexanes/ethyl acetate as aneluent.

3-Amino-N-methyl-4-methylamino-benzamide (460 mg) was prepared byfollowing General Procedure B starting fromN-methyl-4-methylamino-3-nitro-benzamide (535 mg) and Pd/C (10% byweight, 54 mg). The crude product was used in the next step withoutfurther purification.

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl amide (74 mg) was prepared by following General Procedure Dstarting from 3-amino-N-methyl-4-methylamino-benzamide (460 mg),2-amino-6-(trifluoromethoxy)benzothiazole (499 mg),1,1′-thiocarbonyl-diimidazole (454 mg), and EDC (611 mg). LC/MS: m/z423.0. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.39 (bs, 1H), 8.42 (s, 1H), 8.09(s, 1H), 7.93 (s, 1H), 7.75 (d, 2H), 7.50 (d, 1H), 7.36 (d, 1H), 3.68(bs, 3H), 2.81 (d, 3H).

Example 21-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester

4-Methylamino-3-nitro-benzoic acid methyl ester (822 mg) was prepared byfollowing General Procedure A starting from methyl4-chloro-3-nitrobenzoate (1.0 g) and methylamine (2 M in THF, 6.95 mL)in DMF. The crude product was used in the next step without furtherpurification.

3-amino-4-methylamino-benzoic acid methyl ester (677 mg) was prepared byfollowing General Procedure B starting from4-methylamino-3-nitro-benzoic acid methyl ester (822 mg) and Pd/C (10%by weight, 82 mg). The crude product was used in the next step withoutfurther purification.

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (1.47 g) was prepared by following General Procedure Dstarting from 3-amino-4-methylamino-benzoic acid methyl ester (1.5 g),2-amino-6-(trifluoromethoxy)benzothiazole (1.62 g),1,1′-thiocarbonyl-diimidazole (1.48 g), and EDC (1.99 g). LC/MS: m/z423.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.20 (s, 1H), 7.92 (s, 1H), 7.85(bs, 1H), 7.78-7.63 (m, 1H), 7.51 (d, 1H), 7.35 (d, 2H), 3.86 (s, 3H),3.63 (bs, 3H).

Example 31-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (185 mg) was prepared by following General Procedure E startingfrom1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (200 mg) and lithium hydroxide (80 mg). LC/MS: m/z409.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.16 (s, 1H), 7.95 (s, 1H), 7.86 (d,1H), 7.78-7.61 (m, 2H), 7.51 (d, 1H), 7.37 (d, 1H), 3.67 (s, 3H), —COOHproton signal was not observed.

Example 41-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide (27 mg) was prepared by following GeneralProcedure N starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (90 mg), 2-ethoxyethylamine (20 mg), DPPA (61 mg), and DIEA (28mg). LC/MS: m/z 481.0. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.37 (bs, 1H), 8.47(s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 7.47(d, 1H), 7.35 (s, 1H), 3.62 (bs, 3H), 3.54-3.37 (m, 6H), 1.11 (t, 3H).

Example 51-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid cyclopropylmethyl-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid cyclopropylmethyl-amide (24 mg) was prepared by following GeneralProcedure N starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (90 mg), cyclopropane-methylamine (16 mg), DPPA (48 uL), and DIEA(39 uL). LC/MS: m/z 462.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.16 (bs, 1H),8.30 (s, 1H), 7.87 (s, 1H), 7.68 (s, 1H), 7.55 (d, 1H), 7.50 (d, 1H),7.26 (d, 1H), 7.12 (d, 1H), 3.40 (bs, 3H), 2.94 (t, 2H), 0.89-0.78 (m,1H), 0.21 (d, 2H), 0.02 (d, 2H).

Example 61-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide (17 mg) was prepared by following General Procedure Nstarting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), ethylamine (2 M in THF, 123 uL), DPPA (53 uL), and DIEA(43 uL). LC/MS: 436.9 m/z (M+1)⁺. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.43 (s,1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.79-7.65 (m, 2H), 7.46 (d, 1H), 7.35(s, 1H), 3.62 (bs, 3H), 3.30-3.23 (m, 2H), 1.13 (t, 3H), —NH protonsignal was not observed.

Example 7[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazol-5-yl]-pyrrolidin-1-yl-methanone

[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazol-5-yl]-pyrrolidin-1-yl-methanone(34 mg) was prepared by following General Procedure N starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), pyrrolidine (17 mg), DPPA (53 uL), and DIEA (43 uL).LC/MS: m/z 462.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.28 (bs, 1H), 7.90 (s,1H), 7.80-7.56 (m, 2H), 7.42 (s, 2H), 7.33 (d, 1H), 3.63 (s, 3H),3.55-3.33 (m, 4H), 1.95-1.74 (m, 4H).

Example 81-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (22 mg) was prepared by following GeneralProcedure N starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 2-methoxy-ethylamine (18 mg), DPPA (53 uL), and DIEA (43uL). LC/MS: m/z 466.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.36 (bs, 1H), 8.47(s, 1H), 8.08 (s, 1H), 7.89 (s, 1H), 7.76 (s, 1H), 7.71 (d, 1H), 7.47(d, 1H), 7.34 (d, 1H), 3.62 (bs, 3H), 3.53-3.38 (m, 4H), 3.27 (s, 3H).

Example 91-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-fluoro-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-fluoro-ethyl)-amide (31 mg) was prepared by following GeneralProcedure N starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 2-fluoroethylamine hydrochloride (24 mg), DPPA (53 uL),and DIEA (43 uL). LC/MS: m/z 454.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.37(bs, 1H), 8.67 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.79 (d, 1H), 7.71(d, 1H), 7.49 (d, 1H), 7.34 (d, 1H), 4.61 (t, 1H), 4.49 (t, 1H), 3.62(bs, 3H), 3.58-3.48 (m, 2H).

Example 101-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethyl)-amide (27 mg) was prepared by following GeneralProcedure N starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), ethanolamine (15 mg), DPPA (53 uL), and DIEA (43 uL).LC/MS: m/z 452.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.37 (s, 1H), 8.07 (s,1H), 7.91 (s, 1H), 7.81-7.56 (m, 2H), 7.46 (d, 1H), 7.34 (d, 1H), 4.72(s, 1H), 3.64 (s, 3H), 3.58-3.48 (m, 2H), 3.40-3.32 (m, 2H), —NH protonsignal was not observed.

Example 111-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-pyrazol-1-yl-propyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-pyrazol-1-yl-propyl)-amide (99 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 3-(1H-pyrazol-1-yl)propan-1-amine dihydrochloride (50mg), HBTU (111 mg), and DIEA (64 uL). LC/MS: m/z 517.0. ¹H NMR (DMSO-d₆,400 MHz): δ 12.36 (bs, 1H), 8.48 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H),7.81-7.63 (m, 3H), 7.47 (d, 1H), 7.43 (d, 1H), 7.35 (d, 1H), 6.22 (t,1H), 4.18 (t, 2H), 3.62 (bs, 3H), 3.26 (q, 2H), 2.09-1.97 (m, 2H).

Example 121-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid propylamide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid propylamide (86 mg) was prepared by following General Procedure Fstarting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (100 mg), propylamine (16 mg), HBTU (111 mg), and DIEA (64 uL).LC/MS: m/z 450.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.38 (bs, 1H), 8.42 (s,1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.75 (d, 1H), 7.72 (d, 1H), 7.46 (d,1H), 7.34 (d, 1H), 3.62 (bs, 3H), 3.22 (q, 2H), 1.60-1.45 (m, 2H), 0.90(t, 3H).

Example 131-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-hydroxy-propyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-hydroxy-propyl)-amide (98 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 3-amino-1-propanol (20 mg), HBTU (111 mg), and DIEA (64uL). LC/MS: m/z 466.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.40 (bs, 1H), 8.39(s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.78-7.60 (m, 2H), 7.45 (d, 1H),7.34 (d, 1H), 4.48 (s, 1H), 3.63 (bs, 3H), 3.48 (q, 2H), 3.38-3.30 (m,2H), 1.76-1.64 (m, 2H).

Example 141-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-ethoxy-propyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-ethoxy-propyl)-amide (97 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 3-ethoxy-propylamine (28 mg), HBTU (111 mg), and DIEA (64uL). LC/MS: m/z 494.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.36 (bs, 1H), 8.41(s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.78-7.64 (m, 2H), 7.46 (d, 1H),7.34 (d, 1H), 3.62 (bs, 3H), 3.45-3.37 (m, 4H), 3.36-3.31 (m, 2H),1.83-1.70 (m, 2H), 1.10 (t, 3H).

Example 151-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid morpholin-4-ylamide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid morpholin-4-ylamide (100 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 4-aminomorpholine (28 mg), HBTU (111 mg), and DIEA (64uL). LC/MS: m/z 493.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.40 (bs, 1H), 9.49(s, 1H), 8.02 (s, 1H), 7.90 (s, 1H), 7.78-7.59 (m, 2H), 7.47 (d, 1H),7.34 (d, 1H), 3.78-3.56 (m, 7H), 2.93-2.84 (m, 4H).

Example 161-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2,2,2-trifluoro-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2,2,2-trifluoro-ethyl)-amide (102 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 2,2,2-trifluoroethylamine (27 mg), HBTU (111 mg), andDIEA (64 uL). LC/MS: m/z 490.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.40 (bs,1H), 9.05 (s, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.81 (d, 1H), 7.72 (d,1H), 7.51 (d, 1H), 7.34 (d, 1H), 4.18-4.01 (m, 2H), 3.62 (bs, 3H).

Example 171-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (tetrahydro-pyran-4-ylmethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (tetrahydro-pyran-4-ylmethyl)-amide (91 mg) was prepared byfollowing General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 4-amino-methyltetrahydropyran hydrochloride (41 mg), HBTU(111 mg), and DIEA (64 uL). LC/MS: m/z 507.0. ¹H NMR (DMSO-d₆, 400 MHz):δ 8.47 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.77 (d, 1H), 7.73 (d, 1H),7.48 (d, 1H), 7.35 (d, 1H), 3.86 (d, 2H), 3.63 (bs, 3H), 3.28 (t, 2H),3.18 (t, 2H), 1.91-1.62 (m, 1H), 3.28 (d, 2H), 1.30-1.14 (m, 2H), —NHproton signal was not observed.

Example 181-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (tetrahydro-furan-2-ylmethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (tetrahydro-furan-2-ylmethyl)-amide (73 mg) was prepared byfollowing General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), tetrahydrofurfurylamine (27 mg), HBTU (111 mg), and DIEA(64 uL). LC/MS: m/z 492.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.37 (bs, 1H),8.47 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.77 (d, 1H), 7.72 (d, 1H),7.47 (d, 1H), 7.34 (d, 1H), 4.03-3.94 (m, 1H), 3.78 (q, 1H), 3.74-3.57(m, 5H), 3.38-3.31 (m, 1H), 2.00-1.73 (m, 3H), 1.68-1.53 (m, 1H).

Example 191-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-methoxy-propyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-methoxy-propyl)-amide (91 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 3-methoxy-propylamine (24 mg), HBTU (111 mg), and DIEA(64 uL). LC/MS: m/z 480.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.37 (bs, 1H),8.42 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.78-7.63 (m, 2H), 7.46 (d,1H), 7.34 (d, 1H), 3.62 (bs, 3H), 3.38 (t, 2H), 3.34-3.27 (m, 2H), 3.24(s, 3H), 1.82-1.71 (m, 2H).

Example 201-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-1-methyl-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-1-methyl-ethyl)-amide (86 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 1-methoxy-2-propylamine (24 mg), HBTU (111 mg), and DIEA(64 uL). LC/MS: m/z 480.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.39 (bs, 1H),8.18 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.76 (d, 1H), 7.71 (d, 1H),7.46 (d, 1H), 7.34 (d, 1H), 4.30-4.15 (m, 1H), 3.62 (bs, 3H), 3.42 (dd,1H), 3.29 (dd, 1H), 3.27 (s, 3H), 1.14 (d, 3H).

Example 211-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-propyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-propyl)-amide (67 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 1-amino-2-propanol (20 mg), HBTU (111 mg), and DIEA (64uL). LC/MS: m/z 466.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.40 (bs, 1H), 8.35(s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.86-7.66 (m, 2H), 7.48 (d, 1H),7.36 (d, 1H), 4.77 (d, 1H), 3.87-3.77 (m, 1H), 3.64 (bs, 3H), 3.29-3.17(m, 2H), 1.09 (d, 3H).

Example 221-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-2-methyl-propyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-2-methyl-propyl)-amide (68 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 2-methoxy-2-methyl-propylamine (58 mg), HBTU (111 mg),and DIEA (64 uL). LC/MS: m/z 494.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.40(bs, 1H), 8.17 (t, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.73(d, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 3.64 (bs, 3H), 3.36 (d, 2H), 3.18(s, 3H), 1.14 (d, 6H).

Example 231-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (765 mg) was prepared by following General Procedure Dstarting from 3-amino-4-methylamino-benzoic acid methyl ester (991 mg),2-amino-6-(trifluoromethyl)benzothiazole (1.0 g),1,1′-thiocarbonyldiimidazole (1.09 g), and EDC (1.32 g). LC/MS: m/z407.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.37 (bs, 1H), 8.15 (s, 1H), 7.97(d, 1H), 7.95 (d, 1H), 7.85 (d, 1H), 7.62-7.43 (m, 2H), 3.86 (s, 3H),3.62 (bs, 3H).

Example 241-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicAcid

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (434 mg) was prepared by following General Procedure E startingfrom1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (765 mg) and lithium hydroxide (316 mg). LC/MS: m/z393.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.77 (bs, 1H), 12.49 (bs, 1H),8.34-8.14 (m, 2H), 7.93-7.73 (m, 2H), 7.67 (d, 1H), 7.52 (d, 1H), 3.64(bs, 3H).

Example 251-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (78 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 2-methoxy-ethylamine (21 mg), HBTU (116 mg), and DIEA (67uL). LC/MS: m/z 450.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.45 (bs, 1H), 8.47(s, 1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.78 (s, 2H), 7.67 (d, 1H), 7.48(d, 1H), 3.66 (bs, 3H), 3.51-3.39 (m, 4H), 3.27 (s, 3H).

Example 261-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide (77 mg) was prepared by following General Procedure Fstarting from1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (100 mg), ethylamine (2 M in THF, 254 uL), HBTU (116 mg), and DIEA(67 uL). LC/MS: m/z 421.0. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.46 (bs, 1H),8.42 (s, 1H), 8.24 (s, 1H), 8.08 (s, 1H), 7.74 (s, 2H), 7.64 (d, 1H),7.48 (d, 1H), 3.66 (bs, 3H), 3.30 (q, 2H), 1.13 (t, 3H).

Example 271-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethyl)-amide

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethyl)-amide (91 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), ethanolamine (17 mg), HBTU (116 mg), and DIEA (67 uL).LC/MS: m/z 436.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.46 (bs, 1H), 8.38 (s,1H), 8.24 (s, 1H), 8.09 (s, 1H), 7.77 (s, 2H), 7.67 (d, 1H), 7.48 (d,1H), 4.72 (t, 1H), 3.65 (bs, 3H), 3.52 (q, 2H), 3.34 (q, 2H).

Example 282-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester (842 mg) was prepared by following General Procedure Dstarting from 3-amino-4-methylamino-benzoic acid methyl ester (650 mg),2-amino-6-chloro-benzothiazole (556 mg), 1,1′-thiocarbonyldiimidazole(715 mg), and EDC (865 mg). LC/MS: m/z 373.7. ¹H NMR (DMSO-d₆, 400 MHz):δ 12.39 (bs, 1H), 8.19 (s, 1H), 7.92 (s, 1H), 7.84 (s, 1H), 7.64 (s,1H), 7.50 (d, 1H), 7.38 (d, 1H), 3.86 (s, 3H), 3.62 (bs, 3H).

Example 292-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (250 mg) was prepared by following General Procedure E startingfrom2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester (842 mg) and lithium hydroxide (379 mg). LC/MS: m/z359.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.12 (s, 1H), 7.92 (d, 1H), 7.83 (d,1H), 7.55 (s, 1H), 7.48 (d, 1H), 7.38 (dd, 1H), 3.65 (s, 3H), —COOH and—NH proton signal was not observed.

Example 302-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethyl)-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethyl)-amide (9 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (90 mg), ethanolamine (17 mg), HBTU (114 mg), and DIEA (66 uL).LC/MS: m/z 402.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.35 (bs, 1H), 8.36 (s,1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.74 (s, 1H), 7.63 (s, 1H), 7.45 (d,1H), 7.37 (dd, 1H), 4.72 (t, 1H), 3.63 (bs, 3H), 3.52 (q, 2H), 3.34 (q,2H).

Example 312-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (51 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzo-imidazole-5-carboxylicacid (90 mg), 2-methoxyethylamine (21 mg), HBTU (114 mg), and DIEA (66uL). LC/MS: m/z 416.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.36 (bs, 1H), 8.46(s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.46(d, 1H), 7.38 (dd, 1H), 3.62 (bs, 3H), 3.50-3.39 (m, 4H), 3.27 (s, 3H).

Example 322-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid ethylamide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid ethylamide (64 mg) was prepared by following General Procedure Fstarting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (90 mg), ethylamine (2 M in THF, 251 uL), HBTU (114 mg), and DIEA(66 uL). LC/MS: m/z 386.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.38 (bs, 1H),8.40 (s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.72 (d, 1H), 7.57 (bs, 1H),7.44 (d, 1H), 7.37 (dd, 1H), 3.64 (bs, 3H), 3.30 (q, 2H), 1.13 (t, 3H).

Example 332-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester

2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester (579 mg) was prepared by following General Procedure Dstarting from 3-amino-4-methylamino-benzoic acid methyl ester (650 mg),2-amino-5,6-difluorobenzothiazole (560 mg), 1,1′-thiocarbonyldiimidazole(715 mg), and EDC (865 mg). LC/MS: m/z 375.8. ¹H NMR (DMSO-d₆, 400 MHz):δ 12.51 (bs, 1H), 8.25 (s, 1H), 8.19 (s, 1H), 7.85 (s, 1H), 7.68 (d,1H), 7.52 (d, 1H), 3.86 (s, 3H), 3.67 (bs, 3H).

Example 342-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid

2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (265 mg) was prepared by following General Procedure E startingfrom2-(5,6-difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester (579 mg) and lithium hydroxide (260 mg). LC/MS: m/z361.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.75 (bs, 1H), 12.35 (bs, 1H), 8.15(s, 1H), 7.96 (t, 1H), 7.85 (d, 1H), 7.57 (s, 1H), 7.48 (d, 1H), 3.62(bs, 3H).

Example 352-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid ethylamide

2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid ethylamide (55 mg) was prepared by following General Procedure Fstarting from2-(5,6-difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (90 mg), ethylamine (2 M in THF, 250 uL), HBTU (114 mg), and DIEA(65 uL). LC/MS: m/z 388.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.34 (bs, 1H),8.42 (s, 1H), 8.04 (s, 1H), 7.95 (dd, 1H), 7.74 (d, 1H), 7.55 (s, 1H),7.45 (d, 1H), 3.62 (s, 3H), 3.30 (q, 2H), 1.13 (t, 3H).

Example 362-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethyl)-amide

2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethyl)-amide (71 mg) was prepared by following GeneralProcedure F starting from2-(5,6-difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (90 mg), ethanolamine (17 mg), HBTU (114 mg), and DIEA (65 uL).LC/MS: m/z 404.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.34 (bs, 1H), 8.38 (s,1H), 8.05 (s, 1H), 7.95 (t, 1H), 7.76 (s, 1H), 7.56 (s, 1H), 7.46 (d,1H), 4.72 (t, 1H), 3.62 (bs, 3H), 3.52 (q, 2H), 3.34 (q, 2H).

Example 372-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (60 mg) was prepared by following GeneralProcedure F starting from2-(5,6-difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (90 mg), 2-methoxyethylamine (21 mg), HBTU (114 mg), and DIEA (65uL). LC/MS: m/z 418.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.34 (bs, 1H), 8.48(t, 1H), 8.05 (s, 1H), 7.95 (dd, 1H), 7.77 (d 1H), 7.58 (dd, 1H), 7.47(d, 1H), 3.61 (bs, 3H), 3.50-3.39 (m, 4H), 3.27 (s, 3H).

Example 383-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylicacid methylamide

3-Methylamino-4-nitro-benzoic acid (1.1 g) was prepared by followingGeneral Procedure A starting from 3-chloro-4-nitro-benzoic acid (1.0 g)and methylamine (2 M in THF, 8.1 mL) in THF. The crude product was usedin the next step without further purification.

N-Methyl-3-methylamino-4-nitro-benzamide (407 mg) was prepared byfollowing General Procedure N starting from3-methylamino-4-nitro-benzoic acid (500 mg), DPPA (550 uL), DIEA (445uL), and methylamine (2 M in THF, 2.55 mL).

4-Amino-N-methyl-3-methylamino-benzamide (298 mg, 86%) was prepared byfollowing General Procedure B starting fromN-methyl-3-methylamino-4-nitro-benzamide (407 mg) and Pd/C (10% byweight, 40 mg). The crude product was used directly in the next step.

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylicacid methylamide (11 mg) was prepared by following General Procedure Dstarting from 4-amino-N-methyl-3-methylamino-benzamide (298 mg),2-amino-6-(trifluoromethoxy)benzothiazole (303 mg),1,1′-thiocarbonyl-diimidazole (329 mg), and EDC (398 mg). LC/MS: m/z422.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.39 (s, 1H), 8.01 (s, 1H), 7.88 (s,1H), 7.69 (s, 1H), 7.54 (d, 1H), 7.45 (s, 1H), 7.33 (d, 1H), 6.73 (d,1H), 3.63 (bs, 3H), 3.46 (s, 3H).

Example 396-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

2-Fluoro-4-methylamino-5-nitro-benzoic acid (750 mg) was prepared byfollowing General Procedure A starting from 2,4-difluoro-5-nitro-benzoicacid (1.0 g) and methylamine (2 M in THF, 2.46 mL) in THF.

2-Fluoro-N-(2-methoxy-ethyl)-4-methylamino-5-nitro-benzamide wasprepared by following General Procedure F starting from2-fluoro-4-methylamino-5-nitro-benzoic acid (75 mg), HBTU (159 mg), DIEA(92 uL), and 2-methoxyethylamine (26 mg). The crude product was useddirectly in the next step without further purification.

5-Amino-2-fluoro-N-(2-methoxy-ethyl)-4-methylamino-benzamide (72 mg) wasprepared by following General Procedure B starting from2-fluoro-N-(2-methoxy-ethyl)-4-methylamino-5-nitro-benzamide and Pd/C(10% by weight, 10 mg). Th crude product was used in the next stepwithout further purification.

6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (41 mg) was prepared by following GeneralProcedure D starting from5-amino-2-fluoro-N-(2-methoxy-ethyl)-4-methylamino-benzamide (72 mg),2-amino-6-(trifluoromethoxy)-benzothiazole (59 mg),1,1′-thiocarbonyldiimidazole (64 mg), and EDC (77 mg). LC/MS: m/z 484.8.¹H NMR (DMSO-d₆, 400 MHz): δ 12.35 (bs, 1H), 8.16 (s, 1H), 7.91 (d, 1H),7.88 (s, 1H), 7.73 (d, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 3.61 (bs, 3H),3.51-3.40 (m, 4H), 3.30 (s, 3H).

Example 406-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester

2,4-Difluoro-5-nitro-benzoic acid methyl ester (440 mg) was prepared byfollowing General Procedure K starting from 2,4-difluoro-5-nitro-benzoicacid (500 mg) and thionyl chloride (233 uL).

2-Fluoro-4-methylamino-5-nitro-benzoic acid (375 mg) was prepared byfollowing General Procedure A starting from 2,4-difluoro-5-nitro-benzoicacid methyl ester (440 mg) and methylamine (2 M in THF, 1.01 mL) in DMF.

5-Amino-2-fluoro-4-methylamino-benzoic acid methyl ester (115 mg) wasprepared by following General Procedure B starting from2-fluoro-4-methylamino-5-nitro-benzoic acid methyl ester (150 mg) andPd/C (10% by weight, 15 mg). The crude product was used in the next stepwithout further purification.

6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (140 mg) was prepared by following General Procedure Dstarting from 5-amino-2-fluoro-4-methylamino-benzoic acid methyl ester(115 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (115 mg),1,1′-thiocarbonyldiimidazole (126 mg), and EDC (153 mg). LC/MS: m/z441.8.

Example 416-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid

6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (121 mg) was prepared by following General Procedure E startingfrom6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (140 mg) and lithium hydroxide (53 mg). LC/MS: m/z427.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.01 (d, 1H), 7.95 (s, 1H), 7.61 (d,1H), 7.48 (d, 1H), 7.38 (d, 1H), 3.65 (s, 3H), —COOH and —NH protonsignal was not observed.

Example 426-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide

6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid ethylamide (65 mg) was prepared by following General Procedure Fstarting from6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), ethylamine (2 M in THF, 235 uL), HBTU (107 mg), and DIEA(62 uL). LC/MS: m/z 454.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.34 (bs, 1H),8.17 (s, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.73 (s, 1H), 7.48 (s, 1H),7.36 (d, 1H), 3.61 (bs, 3H), 3.33-3.21 (m, 2H), 1.14 (t, 3H).

Example 431-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-ethyl)-amide (92 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 4-(2-amino-ethyl)morpholine (36 uL), HBTU (112 mg), andDIEA (65 uL). LC/MS: m/z 521.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.40 (bs,1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 7.79 (d, 1H), 7.73 (d,1H), 7.52 (d, 1H), 7.36 (d, 1H), 3.85-3.48 (m, 7H), 2.89 (s, 2H), 2.73(s, 2H), 2.51-2.48 (m, 4H).

Example 441-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-trifluoromethoxy-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-trifluoromethoxy-ethyl)-amide (87 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 2-(trifluoromethoxy)ethylamine hydrochloride (45 mg),HBTU (112 mg), and DIEA (65 uL). LC/MS: m/z 520.8. ¹H NMR (DMSO-d₆, 400MHz): δ 12.41 (bs, 1H), 8.72 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.78(d, 1H), 7.74 (d, 1H), 7.51 (d, 1H), 7.36 (d, 1H), 4.23 (t, 2H),3.81-3.55 (m, 5H).

Example 451-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-2-methyl-propyl)-amide

1-Amino-2-methyl-propan-2-ol (244 mg) was prepared by following GeneralProcedure G starting from acetone cyanohydrin (3.34 g) and lithiumaluminum hydride (3.13 g).

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-2-methyl-propyl)-amide (97 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 1-amino-2-methyl-propan-2-ol (24 mg), HBTU (112 mg), andDIEA (65 uL). LC/MS: m/z 480.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.39 (bs,1H), 8.18 (t, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.73 (d,1H), 7.49 (d, 1H), 7.36 (d, 1H), 4.60 (s, 1H), 3.64 (s, 3H), 3.29 (d,2H), 1.14 (s, 6H).

Example 461-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide (220 mg) was prepared byfollowing General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (250 mg), 2-(2-aminoethoxy)ethanol (71 mg), HBTU (279 mg), and DIEA(160 uL). LC/MS: m/z 496.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.39 (bs, 1H),8.47 (t, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.73 (d, 1H),7.49 (d, 1H), 7.36 (d, 1H), 4.61 (t, 1H), 3.64 (s, 3H), 3.57 (t, 2H),3.51 (t, 2H), 3.49-3.41 (m, 4H).

Example 471-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-fluoro-ethoxy)-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-fluoro-ethoxy)-ethyl]-amide (53 mg) was prepared by followingGeneral Procedure H starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide (50 mg) andbis(2-methoxyethyl)aminosulfur trifluoride (47 uL). LC/MS: m/z 498.9. ¹HNMR (DMSO-d₆, 400 MHz): δ 12.39 (bs, 1H), 8.51 (s, 1H), 8.09 (s, 1H),7.93 (s, 1H), 7.86-7.62 (m, 2H), 7.49 (d, 1H), 7.36 (d, 1H), 4.63-4.46(m, 1H), 3.80-3.69 (m, 2H), 3.68-3.52 (m, 6H), 3.46 (q, 2H).

Example 481-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (furan-2-ylmethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (furan-2-ylmethyl)-amide (108 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), furfurylamine (26 mg), HBTU (111 mg), and DIEA (64 uL).LC/MS: m/z 489.0. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.37 (bs, 1H), 8.92 (s,1H), 8.09 (s, 1H), 7.90 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.57 (s,1H), 7.47 (d, 1H), 7.34 (d, 1H), 6.39 (dd, 1H), 6.27 (d, 1H), 4.48 (d,2H), 3.62 (s, 3H).

Example 491-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ([1,4]dioxan-2-ylmethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ([1,4]dioxan-2-ylmethyl)-amide (88 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), c-[1,4]dioxan-2-yl-methylamine (32 mg), HBTU (111 mg),and DIEA (64 uL). LC/MS: m/z 508.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.38(bs, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.87-7.61 (m, 2H),7.49 (d, 1H), 7.37 (d, 1H), 3.85-3.21 (m, 12H).

Example 501-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-2-hydroxy-propyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-2-hydroxy-propyl)-amide (70 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl-amino)-1H-benzoimidazole-5-carboxylicacid (100 mg), (S)-(+)-1-amino-2-propanol (20 mg), HBTU (111 mg), andDIEA (64 uL). LC/MS: m/z 466.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.39 (s,1H), 8.36 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.73 (d,1H), 7.49 (d, 1H), 7.36 (d, 1H), 4.77 (d, 1H), 3.87-3.78 (m, 1H), 3.64(bs, 3H), 3.27-3.20 (m, 2H), 1.09 (d, 3H).

Example 511-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((R)-2-hydroxy-propyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((R)-2-hydroxy-propyl)-amide (78 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-yl-amino)-1H-benzoimidazole-5-carboxylicacid (100 mg), (R)-(−)-1-amino-2-propanol (20 mg), HBTU (111 mg), andDIEA (64 uL). LC/MS: m/z 466.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.39 (s,1H), 8.36 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.86-7.65 (m, 2H), 7.48(d, 1H), 7.36 (d, 1H), 4.77 (d, 1H), 3.89-3.77 (m, 1H), 3.64 (bs, 3H),3.26-3.19 (m, 2H), 1.09 (d, 3H).

Example 521-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (trans-4-hydroxy-cyclohexyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (trans-4-hydroxy-cyclohexyl)-amide (42 mg) was prepared byfollowing General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), trans-4-amino-cyclohexanol (23 mg), HBTU (84 mg), and DIEA(48 uL). LC/MS: m/z 506.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.40 (s, 1H),8.17 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.82-7.64 (m, 2H), 7.47 (d,1H), 7.36 (d, 1H), 4.57 (d, 1H), 3.81-3.68 (m, 1H), 3.64 (bs, 3H),3.46-3.35 (m, 1H), 1.92-1.78 (m, 4H), 1.39 (q, 2H), 1.26 (q, 2H).

Example 531-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(tetrahydro-furan-2-ylmethoxy)-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(tetrahydro-furan-2-ylmethoxy)-ethyl]-amide (21 mg) was preparedby following General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 2-(tetrahydro-furan-2-ylmethoxy)-ethylamine (29 mg), HBTU(84 mg), and DIEA (48 uL). LC/MS: m/z 536.8. ¹H NMR (DMSO-d₆, 400 MHz):δ 12.39 (s, 1H), 8.46 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.83-7.65 (m,2H), 7.49 (d, 1H), 7.36 (d, 1H), 3.98-3.90 (m, 1H), 3.79-3.68 (m, 2H),3.64 (bs, 3H), 3.61-3.52 (m, 2H), 3.49-3.38 (m, 5H), 1.94-1.68 (m, 2H),1.60-1.47 (m, 1H).

Example 541-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-propyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-propyl)-amide (31 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 2-ethoxy-propylamine (21 mg), HBTU (84 mg), and DIEA (48uL). LC/MS: m/z 494.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.39 (s, 1H), 8.43(s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.83-7.66 (m, 2H), 7.48 (d, 1H),7.36 (d, 1H), 3.79-3.43 (m, 5H), 3.41-3.30 (m, 2H), 3.29-3.18 (m, 1H),1.14-1.08 (m, 6H).

Example 552-({[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-morpholine-4-carboxylicacid tert-butyl ester

2-({[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-morpholine-4-carboxylicacid tert-butyl ester (76 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoro-methoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 2-aminomethyl-morpholine-4-carboxylic acid tert-butylester (44 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 607.9. ¹H NMR(DMSO-d₆, 400 MHz): δ 12.41 (s, 1H), 8.59 (s, 1H), 8.09 (s, 1H), 7.92(s, 1H), 7.85-7.63 (m, 2H), 7.50 (d, 1H), 7.37 (d, 1H), 3.95-3.78 (m,2H), 3.76-3.58 (m, 5H), 3.56-3.45 (m, 1H), 3.44-3.35 (m, 4H), 1.22 (s,9H).

Example 561-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (morpholin-2-ylmethyl)-amide hydrochloride

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (morpholin-2-ylmethyl)-amide dihydrochloride (57 mg) was preparedby following General Procedure L starting from2-({[1-methyl-2-(6-trifluoro-methoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-morpholine-4-carboxylicacid tert-butyl ester (63 mg) and HCl (4 M in dioxanes, 260 uL). LC/MS:m/z 507.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 9.37 (bs, 2H), 8.68 (t, 1H),8.11 (s, 1H), 7.95 (s, 1H), 7.80 (d, 1H), 7.64 (d, 1H), 7.52 (d, 1H),7.38 (d, 1H), 4.04-3.86 (m, 2H), 3.76 (t, 1H), 3.69 (s, 3H), 3.52-3.31(m, 2H), 3.28 (d, 1H), 3.18 (d, 1H), 3.06-2.90 (m, 1H), 2.80 (q, 1H).

Example 576-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide (52 mg) was prepared by following GeneralProcedure F starting from6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 2-ethoxyethylamine (17 mg), HBTU (80 mg), and DIEA (46uL). LC/MS: m/z 498.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.35 (bs, 1H), 8.14(d, 1H), 7.92 (s, 1H), 7.89 (d, 1H), 7.73 (d, 1H), 7.50 (d, 1H), 7.37(s, 1H), 3.60 (bs, 3H), 3.56-3.41 (m, 6H), 1.14 (t, 3H).

Example 586-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide

6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide (32 mg) was prepared by followingGeneral Procedure F starting from6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), glycine dimethylamide acetate (32 mg), HBTU (80 mg), andDIEA (46 uL). LC/MS: m/z 511.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.39 (bs,1H), 8.19-8.00 (m, 2H), 7.93 (s, 1H), 7.74 (d, 1H), 7.54 (d, 1H), 7.36(d, 1H), 4.18 (d, 2H), 3.61 (bs, 3H), 3.01 (s, 3H), 2.89 (s, 3H).

Example 596-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-ethyl)-amide

6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-ethyl)-amide (21 mg) was prepared by followingGeneral Procedure F starting from6-fluoro-1-methyl-2-(6-trifluoro-methoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 4-(2-aminoethyl)morpholine (25 mg), HBTU (80 mg), and DIEA(46 uL). LC/MS: m/z 539.7.

¹H NMR (DMSO-d₆, 400 MHz): δ 12.38 (bs, 1H), 9.54 (s, 1H), 8.41 (s, 1H),7.95 (s, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.36 (d, 1H), 4.01 (d, 2H),3.80-3.51 (m, 7H), 3.25-3.09 (m, 2H), 2.53-2.49 (m, 4H).

Example 606-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-propyl)-amide

6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-propyl)-amide (52 mg) was prepared by following GeneralProcedure F starting from6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 1-amino-2-propanol (15 mg), HBTU (80 mg), and DIEA (46uL). LC/MS: m/z 484.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.93 (bs, 1H),12.35 (bs, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.73 (d, 1H), 7.51 (d, 1H),7.36 (d, 1H), 4.79 (s, 1H), 3.86-3.75 (m, 1H), 3.61 (bs, 3H), 3.29-3.17(m, 2H), 1.10 (d, 3H).

Example 616-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester

2-Methoxy-4-methylamino-5-nitro-benzoic acid methyl ester (120 mg) wasprepared by following General Procedure A starting from2-Fluoro-4-methylamino-5-nitro-benzoic acid methyl ester (200 mg) andsodium methoxide (190 mg) in DMF.

5-Amino-2-methoxy-4-methylamino-benzoic acid methyl ester (95 mg) wasprepared by following General Procedure B starting from2-methoxy-4-methylamino-5-nitro-benzoic acid methyl ester (120 mg) andPd/C (10% by weight, 12 mg). The crude product was used in the next stepwithout further purification.

6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (80 mg) was prepared by following General Procedure Dstarting from 5-amino-2-methoxy-4-methylamino-benzoic acid methyl ester(95 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (82 mg),1,1′-thiocarbonyldiimidazole (90 mg), and EDC (108 mg). LC/MS: m/z453.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.24, (s, 1H), 7.97 (s, 1H), 7.92(s, 1H), 7.71 (d, 1H), 7.36 (d, 1H), 7.24 (s, 1H), 3.90 (s, 3H), 3.80(s, 3H), 3.64 (s, 3H).

Example 626-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid

6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (60 mg) was prepared by following General Procedure E starting from6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (80 mg) and lithium hydroxide (30 mg). LC/MS: m/z439.8.

Example 636-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide

6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide (37 mg) was prepared by followingGeneral Procedure F starting from6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (60 mg), glycine dimethylamide acetate (25 mg), HBTU (63 mg), andDIEA (36 uL). LC/MS: m/z 523.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.29 (bs,1H), 8.84 (t, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.72 (d, 1H), 7.35 (d,1H), 7.30 (s, 1H), 4.21 (d, 2H), 4.04 (s, 3H), 3.65 (s, 3H), 3.00 (s,3H), 2.91 (s, 3H).

Example 64

6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide (37 mg) was prepared by following General Procedure Fstarting from6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), ethylamine (2 M in THF, 171 uL), HBTU (78 mg), and DIEA(45 uL). LC/MS: m/z 466.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.25 (s, 1H),8.22 (t, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H), 7.34 (d, 1H),7.24 (s, 1H), 3.98 (s, 3H), 3.64 (s, 3H), 3.39-3.30 (m, 2H), 1.14 (t,3H).

Example 656-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide (72 mg) was prepared by following GeneralProcedure F starting from6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 2-ethoxyethylamine (17 mg), HBTU (78 mg), and DIEA (45uL). LC/MS: m/z 510.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.27 (s, 1H), 8.34(t, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H), 7.35 (d, 1H), 7.26(s, 1H), 4.0 (s, 3H), 3.64 (s, 3H), 3.56-3.43 (m, 6H), 1.16 (t, 3H).

Example 666-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-ethyl)-amide

6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-ethyl)-amide (69 mg) was prepared by followingGeneral Procedure F starting from6-methoxy-1-methyl-2-(6-trifluoro-methoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 4-(2-aminoethyl)morpholine (25 mg), HBTU (78 mg), and DIEA(45 uL). LC/MS: m/z 551.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.27 (bs, 1H),8.50 (bs, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H), 7.35 (d, 1H),7.28 (s, 1H), 4.02 (s, 3H), 3.76-3.55 (m, 7H), 3.38-3.27 (m, 4H),2.52-2.49 (m, 4H).

Example 676-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (55 mg) was prepared by following GeneralProcedure F starting from6-methoxy-1-methyl-2-(6-trifluoro-methoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 2-methoxy-ethylamine (14 mg), HBTU (78 mg), and DIEA (45uL). LC/MS: m/z 496.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.26 (s, 1H), 8.32(s, 1H), 8.15 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H), 7.34 (s, 1H), 7.26(s, 1H), 4.00 (s, 3H), 3.64 (s, 3H), 3.51-3.47 (m, 4H), 3.31 (s, 3H).

Example 686-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-propyl)-amide

6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (2-hydroxy-propyl)-amide (56 mg) was prepared by following GeneralProcedure F starting from6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 1-amino-2-propanol (14 mg), HBTU (78 mg), and DIEA (45uL). LC/MS: m/z 496.6. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.27 (s, 1H), 8.32(t, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H), 7.35 (d, 1H), 7.26(s, 1H), 4.85 (d, 1H), 4.00 (s, 3H), 3.85-3.76 (m, 1H), 3.64 (s, 3H),3.43-3.34 (m, 1H), 3.24-3.14 (m, 1H), 1.10 (d, 3H).

Example 696-Diethylamino-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester

2-Diethylamino-4-methylamino-5-nitro-benzoic acid methyl ester (1.2 g)was prepared by following General Procedure A starting from2-fluoro-4-methylamino-5-nitro-benzoic acid methyl ester (1.0 g) anddiethylamine (683 uL) in DMF.

5-Amino-2-diethylamino-4-methylamino-benzoic acid methyl ester (1.015 g)was prepared by following General Procedure B starting from2-diethylamino-4-methylamino-5-nitro-benzoic acid methyl ester (1.2 g)and Pd/C (10% by weight, 120 mg). The crude product was used in the nextstep without further purification.

6-Diethylamino-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (1.26 g) was prepared by following General Procedure Dstarting from 5-amino-2-diethylamino-4-methylamino-benzoic acid methylester (1.015 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (656 mg),1,1′-thiocarbonyldiimidazole (714 mg), and EDC (865 mg). LC/MS: m/z494.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.21 (bs, 1H), 7.90 (s, 1H),7.80-7.56 (m, 2H), 7.34 (d, 1H), 7.25 (s, 1H), 3.81 (s, 3H), 3.62 (s,3H), 3.13-2.97 (m, 4H), 0.96 (t, 6H).

Example 706-Diethylamino-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid

6-Diethylamino-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (175 mg) was prepared by following General Procedure E startingfrom6-diethylamino-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (300 mg) and lithium hydroxide (102 mg). LC/MS: m/z480.9. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.45 (bs, 1H), 8.25 (bs, 1H), 7.96(s, 1H), 7.85 (s, 1H), 7.80-7.62 (m, 1H), 7.38 (d, 1H), 3.68 (s, 3H),3.41-3.25 (m, 4H), 0.94 (t, 6H), —COOH proton signal was not observed.

Example 713-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid ethyl ester

6-Methylamino-5-nitro-nicotinic acid ethyl ester (911 mg) was preparedby following General Procedure A starting from6-chloro-5-nitro-nicotinic acid ethyl ester (1.0 g) and methylamine (2 Min THF, 3.25 mL) in DMF.

5-Amino-6-methylamino-nicotinic acid ethyl ester (723 mg) was preparedby following General Procedure B starting from6-methylamino-5-nitro-nicotinic acid ethyl ester (911 mg) and Pd/C (10%by weight, 90 mg). The crude product was used in the next step withoutfurther purification.

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid ethyl ester (560 mg) was prepared by following General Procedure Dstarting from 5-amino-6-methylamino-nicotinic acid ethyl ester (723 mg),2-amino-6-(trifluoromethoxy)benzothiazole (735 mg),1,1′-thiocarbonyldiimidazole (802 mg), and EDC (969 mg). LC/MS: m/z437.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.44 (s, 1H), 7.94 (s, 1H), 7.89(s, 1H), 7.74 (s, 1H), 7.52 (d, 1H), 7.37 (d, 1H), 4.33 (q, 2H), 3.65(s, 3H), 1.36 (t, 3H).

Example 723-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (58 mg, 62%) was prepared by following General Procedure E startingfrom3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid ethyl ester (100 mg) and lithium hydroxide (38 mg). LC/MS: m/z409.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 13.00 (s, 1H), 8.16 (s, 1H), 7.95(d, 1H), 7.86 (dd, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.37 (d, 1H), 3.68(s, 3H).

Example 733-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (2-methoxy-ethyl)-amide

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (2-methoxy-ethyl)-amide (38 mg) was prepared by following GeneralProcedure F starting from3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (58 mg), 2-methoxyethylamine (12 mg), HBTU (65 mg), and DIEA (37uL). LC/MS: m/z 466.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.49 (t, 1H), 8.09(s, 1H), 7.94 (s, 1H), 7.78 (d, 1H), 7.64 (d, 1H), 7.50 (d, 1H), 7.37(d, 1H), 3.67 (s, 3H), 3.54-3.40 (m, 4H), 3.29 (s, 3H).

Example 743-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid dimethylcarbamoylmethyl-amide

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid dimethylcarbamoylmethyl-amide (25 mg) was prepared by followingGeneral Procedure F starting from3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (48 mg), glycine dimethylamide acetate (21 mg), HBTU (53 mg), andDIEA (31 uL). LC/MS: m/z 493.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.46 (t,1H), 8.12 (s, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.51 (d,1H), 7.36 (d, 1H), 4.13 (d, 2H), 3.65 (bs, 3H), 3.03 (s, 3H), 2.87 (s,3H).

Example 753-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (2-ethoxy-ethyl)-amide

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (2-ethoxy-ethyl)-amide (52 mg) was prepared by following GeneralProcedure F starting from3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (75 mg), 2-ethoxyethylamine (18 mg), HBTU (83 mg), and DIEA (48uL). LC/MS: m/z 480.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.41 (bs, 1H), 8.47(t, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.76 (d, 1H), 7.48 (d, 1H), 7.36(d, 1H), 3.66 (s, 3H), 3.56-3.39 (m, 6H), 1.13 (t, 3H).

Example 763-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid ethylamide

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid ethylamide (58 mg) was prepared by following General Procedure Fstarting from3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (75 mg), 2-ethylamine (2 M in THF, 183 uL), HBTU (83 mg), and DIEA(48 uL). LC/MS: m/z 436.6. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.39 (bs, 1H),8.44 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.81-7.65 (m, 1H), 7.48 (d,1H), 7.36 (d, 1H), 3.64 (s, 3H), 3.40-3.23 (m, 2H), 1.15 (t, 3H).

Example 773-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (2-morpholin-4-yl-ethyl)-amide

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (2-morpholin-4-yl-ethyl)-amide (28 mg) was prepared by followingGeneral Procedure F starting from3-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (75 mg), 4-(2-aminoethyl)morpholine (26 mg), HBTU (83 mg), and DIEA(48 uL). LC/MS: m/z 466.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.39 (bs, 1H),8.48 (bs, 1H), 8.09 (s, 1H), 7.94 (d, 1H), 7.81-7.66 (m, 1H), 7.51 (d,1H), 7.35 (d, 1H), 3.83-3.23 (m, 11H), 2.51-2.48 (m, 4H).

Example 783-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (2-hydroxy-propyl)-amide

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (2-hydroxy-propyl)-amide (56 mg) was prepared by following GeneralProcedure F starting from3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (75 mg), 1-amino-2-propanol (15 mg), HBTU (83 mg), and DIEA (48uL). LC/MS: m/z 466.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.36 (s, 1H), 8.10(s, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.36(d, 1H), 4.77 (d, 1H), 3.89-3.77 (m, 1H), 3.64 (s, 3H), 3.27-3.16 (m,2H), 1.10 (d, 3H).

Example 79{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid methyl ester

{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid methyl ester (36 mg) was prepared by following General Procedure Fusing1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), glycine methyl ester (27 mg), HBTU (38 mg), and DIEA (0.1ml). LC/MS: m/z 481. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.85 (br, 1H), 8.08(s, 1H), 7.91 (m, 2H), 7.81-7.70 (m, 2H), 7.49 (d, 1H), 7.35 (d, 1H),4.03 (d, 2H), 3.65 (s, 3H), and 3.62 (s, 3H).

Example 801-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide (41 mg) was prepared by followingGeneral Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), 2-amino-N,N-dimethyl-acetamide (0.33 ml), HBTU (38 mg),and DIEA (0.1 ml). LC/MS: m/z 494. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.42 (t,1H), 8.09 (s, 1H), 7.90 (m, 1H), 7.78 (br, 1H), 7.72 (br, 1H), 7.48 (d,1H), 7.44 (d, 1H), 7.34 (m, 1H), 4.11 (d, 2H), 3.63 (s, 3H), and 3.00(d, 6H).

Example 811-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-1-ethylcarbamoyl-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-1-ethylcarbamoyl-ethyl)-amide (37 mg) was prepared byfollowing General Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), (S)-2-amino-N-ethyl-propionamide (0.37 ml), HBTU (38 mg),and DIEA (0.1 ml). LC/MS: m/z 508. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.38 (d,1H), 8.13 (s, 1H), 7.92 (s, 2H), 7.86 (br, 1H), 7.73 (br, 1H), 7.48 (d,1H), 7.36 (d, 1H), 4.46 (p, 1H), 3.66 (s, 3H), 3.12-3.09 (m, 2H), 1.34(d, 3H), and 1.04 (t, 3H), NH proton signal was not observed.

Example 821-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-dimethylamino-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-dimethylamino-ethyl)-amide (42 mg) was prepared by followingGeneral Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), N,N-dimethyl-ethylenediamine (0.29 ml), HBTU (38 mg), andDIEA (0.1 ml). LC/MS: m/z 480. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.16 (t,1H), 7.81 (s, 1H), 7.61 (d, 1H), 7.49 (d, 1H), 7.29 (d, 1H), 7.15 (d,1H), 7.07 (d, 1H), 3.56 (s, 3H), 3.32 (m, 2H), 2.85 (m, 2H), 2.41 (t,1H), 2.17 (s, 6H).

Example 83{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid

{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (211 mg) was prepared by following General Procedure E startingfrom{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid methyl ester (240 mg), and LiOH (1.0 ml, 2.0 N solution in water).LC/MS: m/z 467.

Example 841-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide (29 mg) was prepared by following General Procedure Fusing1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (39 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg),and DIEA (0.2 ml). LCMS: m/z 407; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.52(d, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.70 (d, 1H), 7.54 (d, 1H), 7.30(d, 1H), 7.22-7.16 (m, 2H), 3.57 (s, 3H), and 2.87 (d, 3H).

Example 851-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide (36 mg) was prepared by following GeneralProcedure F using1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (39 mg), 2-ethoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1ml). LCMS: m/z 465; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.40 (t, 1H), 7.99(s, 1H), 7.82 (d, 1H), 7.66 (d, 1H), 7.44 (br, 2H), 7.36 (d, 1H), 7.30(dd, 1H), 3.61 (s, 3H), 3.46 (q, 2H), 3.41 (t, 2H), 2.82 (m 2H), and1.07 (t, 3H).

Example 862-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methylamide

2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methylamide (26 mg) was prepared by following General Procedure Fusing2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (36 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg),and DIEA (0.2 ml). LCMS: m/z 375; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.30(d, 1H), 8.04 (s, 1H), 7.93 (d, 1H), 7.60 (d, 1H), 7.49 (m, 2H), 7.29(d, 1H), 3.62 (s, 3H), and 2.80 (d, 3H).

Example 872-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide (31 mg) was prepared by following GeneralProcedure F using2-(5,6-Difluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (36 mg), 2-ethoxy-ethyl amine (0.1 ml), HBTU (38 mg), and DIEA (0.2ml). LCMS: m/z 433; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.46 (m, 1H), 8.21(s, 1H), 8.06 (s, 1H), 7.76 (m, 1H), 7.65 (d, 1H), 7.48 (m, 2H), 3.66(s, 3H), 3.47 (t, 2H), 2.88 (m, 4H), and 1.09 (t, 3H).

Example 882-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methylamide

1-Methyl-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide (30 mg) was prepared by following General Procedure Fusing1-methyl-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (36 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg),and DIEA (0.2 ml). LCMS: m/z 373; and ¹H NMR (DMSO-d₆, 400 MHz): δ 9.63(d, 1H), 8.24 (d, 1H), 7.84 (m, 1H), 7.71 (t, 1H) 7.52 (d, 1H), 7.22 (m2H), 5.24 (m, 1H), 3.65 (s, 3H), and 2.81 (d, 3H).

Example 892-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

1-Methyl-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide (33 mg) was prepared by following GeneralProcedure F using1-methyl-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (36 mg), 2-ethoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1ml). LCMS: m/z 431; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.26 (t, 1H), 7.80(s, 1H), 7.65 (t, 1H), 7.56 (br, 2H), 7.48 (d, 1H), 7.18 (m, 1H), 7.14(d, 1H), 3.54 (s, 3H), 3.46 (q, 2H), 3.38 (m 2H), 3.24 (t, 2H), and 1.08(t, 3H).

Example 901-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (1-methanesulfonyl-piperidin-4-yl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (1-methanesulfonyl-piperidin-4-yl)-amide (42 mg) was prepared byfollowing General Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), 1-methanesulfonyl-piperidin-4-ylamine (60 mg), HBTU (38mg), and DIEA (0.1 ml). LC/MS: m/z 570. ¹H NMR (DMSO-d₆, 400 MHz): δ8.32 (br, 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.74 (br, 1H), 7.46 (d, 1H),7.34 (d, 1H), 3.92 (br, 1H), 3.63 (s, 3H), 3.58 (m, 2H), 2.87 (s, 3H),2.82 (m, 2H), 1.83 (m, 2H), and 1.62 (m, 2H), 2 —NH proton signals werenot observed.

Example 91{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid tert-butyl ester

{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid tert-butyl ester (41 mg) was prepared by following GeneralProcedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), glycine-tert-butyl ester (44 mg), HBTU (38 mg), and DIEA(0.1 ml). LC/MS: m/z 523. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.76 (t, 1H),8.20 (br, 1H), 8.12 (m, 1H), 8.05 (s, 1H), 7.88 (d, 1H), 7.73 (d, 1H),7.46 (d, 1H), 7.31 (d, 1H), 3.90 (d, 2H), 3.65 (s, 3H), and 1.42 (s,9H).

Example 924-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

4-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (46 mg) was prepared by following GeneralProcedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (67mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 592. ¹H NMR (DMSO-d₆,400 MHz): δ 8.26 (d, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.74 (br, 1H),7.47 (d, 1H), 7.35 (d, 1H), 3.97 (br, 1H), 3.91 (m, 2H), 3.66 (s, 3H),2.82 (m, 2H), 1.81 (m, 2H), 1.42 (s, 9H), and 1.41 (m, 2H), 2 —NH protonsignals were not observed.

Example 931-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid piperidin-4-ylamide hydrochloride

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid piperidin-4-ylamide hydrochloride (15 mg) was prepared by followingGeneral Procedure L using4-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (30 mg), and hydrochloric acid (0.1 ml, 4.0 Nsolution in dioxane). LC/MS: m/z 492. ¹H NMR (DMSO-d₆, 400 MHz): δ 9.21(br, 1H), 9.00 (br, 1H), 8.42 (m, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 7.72(br, 1H), 7.45 (d, 1H), 7.36 (d, 1H), 3.52 (s, 3H), 3.32 (m, 4H), 2.92(q, 4H), and 1.79 (m, 2H).

Example 943-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

3-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (44 mg) was prepared by following GeneralProcedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), 3-amino-piperidine-1-carboxylic acid tert-butyl ester (67mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 592. ¹H NMR (DMSO-d₆,400 MHz): δ 8.22 (m, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.73 (br, 1H),7.53 (br, 1H), 7.43 (d, 1H), 7.32 (d, 1H), 3.82 (br, 1H), 3.65 (s, 3H),3.20 (m, 2H), 2.80 (m, 2H), 1.81 (m, 1H), and 1.39 (s, 9H) and 1.03 (d,4H).

Example 951-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid piperidin-3-ylamide hydrochloride

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid piperidin-3-ylamide hydrochloride (13 mg) was prepared by followingGeneral Procedure L using3-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (30 mg), and hydrochloric acid (0.1 ml, 4.0 Nsolution dioxane). LC/MS: m/z 492.

Example 961-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (thiazol-2-ylmethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (thiazol-2-ylmethyl)-amide (44 mg) was prepared by followingGeneral Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), 2-aminomethyl-thiazole (38 mg), HBTU (38 mg), and DIEA(0.1 ml). LC/MS: m/z 506. ¹H NMR (DMSO-d₆, 400 MHz): δ 9.36 (br, 1H),8.13 (s, 1H), 7.93 (s, 1H), 7.82 (br, 1H), 7.75 (d, 1H), 7.63 (d, 1H),7.54 (d, 1H), 7.36 (d, 1H), 4.77 (d, 2H), and 3.67 (s, 3H).

Example 973-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid methyl ester

3-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid methyl ester (33 mg) was prepared by following General Procedure Fusing1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benz-imidazole-5-carboxylicacid (41 mg), 3-amino-propionic acid methyl ester (35 mg), HBTU (38 mg),and DIEA (0.1 ml). LC/MS: m/z 495. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.53 (t,1H), 8.12 (br, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.42 (m, 2H), 7.48 (d,1H), 7.38 (d, 1H), 3.65 (s, 3H), 3.62 (s, 3H), 3.04 (m, 2H), and 2.62(t, 2H).

Example 983-{[2-(6-Trifluoromethoxy-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carbonyl]-amino}-propionicacid

3-{[2-(6-Trifluoromethoxy-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carbonyl]-amino}-propionicacid (200 mg) was prepared by following General Procedure E startingfrom3-{[2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1-methyl-1H-benz-imidazole-5-carbonyl]-amino}-propionicacid methyl ester (247 mg), and LiOH (1.0 ml, 2.0 N solution in water).LC/MS: m/z 481. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.51 (t, 1H), 8.10 (br,1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.75 (d, 1H), 7.64 (br, 1H), 7.46 (d,1H), 7.34 (d, 1H), 3.63 (s, 3H), 3.46 (m, 2H), and 2.58 (t, 2H), —COOHproton signal was not observed.

Example 991-Methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester

4-Methylamino-3-nitro-benzoic acid methyl ester (822 mg) was prepared byfollowing General Procedure A starting from methyl4-chloro-3-nitrobenzoate (1.0 g) and methylamine (2 M in THF, 6.95 mL)in DMF. The crude product was used in the next step without furtherpurification.

3-amino-4-methylamino-benzoic acid methyl ester (677 mg) was prepared byfollowing General Procedure B starting from4-methylamino-3-nitro-benzoic acid methyl ester (822 mg) and Pd/C (10%by weight, 82 mg). The crude product was used in the next step withoutfurther purification.

1-Methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (1.35 g) was prepared by following General Procedure Dstarting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g),2-amino-5-(trifluoromethoxy)benzothiazole (1.17 g),1,1′-thiocarbonyldiimidazole (1.07 g), and EDC (1.15 g). LC/MS: m/z 424.¹H NMR (DMSO-d₆, 400 MHz): δ 8.16 (s, 1H), 7.92 (s, 1H), 7.85 (br, 1H),7.78-7.63 (m, 1H), 7.50 (d, 1H), 7.36 (d, 2H), 3.66 (s, 3H), and 3.58(s, 3H).

Example 1001-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-acetylamino-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-acetylamino-ethyl)-amide (44 mg) was prepared by followingGeneral Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), N-(2-amino-ethyl)-acetamide (34 mg), HBTU (38 mg), andDIEA (0.1 ml). LC/MS: m/z 494. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.40 (s,1H), 7.98 (m, 2H), 7.81 (s, 1H), 7.64 (d, 1H), 7.51 (br, 1H), 7.35 (m,1H), 7.25 (d, 1H), 3.62 (s, 3H), 3.22 (t, 4H), and 1.81 (s, 3H), —NHproton signal was not observed.

Example 1011-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methylsulfanyl-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methylsulfanyl-ethyl)-amide (82 mg) was prepared by followingGeneral Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (82 mg), 2-methylthio-ethylamine (30 mg), HBTU (76 mg), and DIEA(0.2 ml). LC/MS: m/z 483. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.58 (s, 1H),8.09 (s, 1H), 7.91 (m, 1H), 7.47 (m, 2H), 7.48 (d, 1H), 7.37 (d, 1H),3.64 (s, 3H), 3.48 (q, 2H), 2.68 (t, 2H), and 2.12 (s, 3H), —NH protonsignal was not observed.

Example 1021-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methanesulfonyl-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methylsulfonyl-ethyl)-amide (37 mg) was prepared by followingGeneral Procedure M using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methylsulfanyl-ethyl)-amide (48 mg), and peracetic acid (0.1 ml,32 wt % solution in acetic acid). LC/MS: m/z 515. ¹H NMR (DMSO-d₆, 400MHz): δ 8.68 (t, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.75 (m, 2H), 7.52 (d,1H), 7.44 (d, 1H), 7.37 (d, 1H), 3.72 (m, 2H), 3.63 (s, 3H), 3.40 (t,2H), and 3.06 (s, 3H).

Example 103(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-carbamicacid tert-butyl ester

(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-carbamicacid tert-butyl ester (92 mg) was prepared by following GeneralProcedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (82 mg), (2-amino-ethyl)-carbamic acid tert-butyl ester (64 mg),HBTU (76 mg), and DIEA (0.2 ml). LC/MS: m/z 552. ¹H NMR (DMSO-d₆, 400MHz): δ 8.40 (br, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.73 (m, 2H), 7.46(d, 1H), 7.34 (d, 1H), 6.91 (t, 1H), 4.24 (t, 2H), 3.64 (s, 3H),3.14-3.09 (q, 2H), and 1.36 (s, 9H), —NH proton signal was not observed.

Example 1041-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-amino-ethyl)-amide hydrochloride

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-amino-ethyl)-amide hydrochloride (27 mg) was prepared byfollowing General Procedure L using(2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-carbamicacid tert-butyl ester (55 mg), and hydrochloric acid (0.1 ml, 4.0 Nsolution dioxane). LC/MS: m/z 452. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.63(br, 1H), 8.42 (br, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.71 (m, 2H), 7.44(d, 1H), 7.35 (d, 1H), 4.19 (t, 2H), 3.64 (s, 3H), and 3.08 (m, 2H), 2—NH proton signals were not observed.

Example 1051-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methylamino-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methylamino-ethyl)-amide (28 mg) was prepared by followingGeneral Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), N-methyl-ethylendiamine (25 mg), HBTU (38 mg), and DIEA(0.1 ml). LC/MS: m/z 466. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.43 (br, 1H),8.20 (br, 1H), 7.95 (s, 1H), 7.88 (m, 1H), 7.69 (m, 2H), 7.56 (d, 1H),7.38 (d, 1H), 7.23 (d, 1H), 3.59 (s, 3H), 3.44 (m, 2H), 2.98 (m, 2H),and 2.70 (d, 3H).

Example 1061-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid trimethylhydrazide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid trimethylhydrazide (33 mg) was prepared by following GeneralProcedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), N,N,N′-trimethylhydrazine dihydrochloride (49 mg), HBTU(38 mg), and DIEA (0.1 ml). LC/MS: m/z 466.

Example 1071-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethylsulfanyl-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethylsulfanyl-ethyl)-amide (72 mg) was prepared by followingGeneral Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benz-imidazole-5-carboxylicacid (82 mg), 2-ethylthio-ethylamine (34 mg), HBTU (76 mg), and DIEA(0.2 ml). LC/MS: m/z 497.

Example 1081-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-methylsulfanyl-propyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-methylsulfanyl-propyl)-amide (69 mg) was prepared by followingGeneral Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (82 mg), 3-methylthio-propylamine (38 mg), HBTU (76 mg), and DIEA(0.2 ml). LC/MS: m/z 497.

Example 1091-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-ethanesulfonyl-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethylsulfonyl-ethyl)-amide (36 mg) was prepared by followingGeneral Procedure M using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (2-ethylsulfanyl-ethyl)-amide (50 mg), and peracetic acid (0.1 ml,32 wt % solution in acetic acid). LC/MS: m/z 529. ¹H NMR (DMSO-d₆, 400MHz): δ 8.72 (br, 1H), 8.09 (d, 1H), 7.92 (m, 1H), 7.75 (t, 2H), 7.50(m, 1H), 7.37 (d, 1H), 3.72 (m, 1H), 3.63 (s, 3H), 3.50 (m, 2H), 3.40(t, 2H), 3.16 (q, 2H), and 1.24 (t, 3H).

Example 1101-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (3-methanesulfonyl-propyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-methanesulfonyl-propyl)-amide (37 mg) was prepared by followingGeneral Procedure M using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-methylsulfanyl-propyl)-amide (48 mg), and peracetic acid (0.1ml, 32 wt % solution in acetic acid). LC/MS: m/z 529. ¹H NMR (DMSO-d₆,400 MHz): δ 12.40 (br, 1H), 8.56 (t, 1H), 8.10 (d, 1H), 7.91 (s, 1H),7.79 (d, 1H), 7.73 (d, 1H), 7.50 (d, 1H), 7.37 (d, 1H), 3.64 (s, 3H),3.19 (t, 2H), 2.99 (s, 3H), 1.99 (t, 2H), and 1.31 (t, 2H).

Example 1112-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester

4-Methylamino-3-nitro-benzoic acid methyl ester (822 mg) was prepared byfollowing General Procedure A using methyl 4-chloro-3-nitrobenzoate (1.0g) and methylamine (2 M in THF, 6.95 mL, 13.9) in DMF (5 mL). The crudeproduct was used in the next step without further purification.

3-amino-4-methylamino-benzoic acid methyl ester (677 mg) was prepared byfollowing General Procedure B starting from4-methylamino-3-nitro-benzoic acid methyl ester (822 mg) and Pd/C (10%by weight). The crude product was used in the next step without furtherpurification.

1-Methyl-2-(5-fluoro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (1.16 g) was prepared by following General Procedure Dstarting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g),2-amino-5-fluoro-benzothiazole (0.84 g), 1,1′-thiocarbonyldiimidazole(1.07 g), and EDC (1.15 g). LC/MS: m/z 358.

Example 1122-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester

4-Methylamino-3-nitro-benzoic acid methyl ester (822 mg) was prepared byfollowing General Procedure A using methyl 4-chloro-3-nitrobenzoate (1.0g) and methylamine (2 M in THF, 6.95 mL) in DMF (5 mL). The crudeproduct was used in the next step without further purification.

3-amino-4-methylamino-benzoic acid methyl ester (677 mg) was prepared byfollowing General Procedure B starting from4-methylamino-3-nitro-benzoic acid methyl ester (822 mg) and Pd/C (10%by weight, 82 mg). The crude product was used in the next step withoutfurther purification.

1-Methyl-2-(6-fluoro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (1.26 g) was prepared by following General Procedure Dstarting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g),2-amino-6-fluoro-benzothiazole (0.84 g), 1,1′-thiocarbonyldiimidazole(1.07 g), and EDC (1.15 g). LC/MS: m/z 358.

Example 1132-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester

4-Methylamino-3-nitro-benzoic acid methyl ester (822 mg) was prepared byfollowing General Procedure A using methyl 4-chloro-3-nitrobenzoate (1.0g) and methylamine (2 M in THF, 6.95 mL) in DMF (5 mL). The crudeproduct was used in the next step without further purification.

3-amino-4-methylamino-benzoic acid methyl ester (677 mg) was prepared byfollowing General Procedure B starting from4-methylamino-3-nitro-benzoic acid methyl ester (822 mg) and Pd/C (10%by weight, 82 mg). The crude product was used in the next step withoutfurther purification.

2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid methyl ester (1.64 g) was prepared by following General Procedure Dstarting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g),2-amino-6-methanesulfonyl-benzothiazole (1.14 g),1,1′-thiocarbonyldiimidazole (1.07 g), and EDC (1.15 g). LC/MS: m/z 418.

Example 1141-Methyl-2-(6-methyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester

4-Methylamino-3-nitro-benzoic acid methyl ester (822 mg) was prepared byfollowing General Procedure A using methyl 4-chloro-3-nitrobenzoate (1.0g) and methylamine (2 M in THF, 6.95 mL) in DMF (5 mL). The crudeproduct was used in the next step without further purification.

3-amino-4-methylamino-benzoic acid methyl ester (677 mg) was prepared byfollowing General Procedure B starting from4-methylamino-3-nitro-benzoic acid methyl ester (822 mg) and Pd/C (10%by weight, 82 mg). The crude product was used in the next step withoutfurther purification.

1-Methyl-2-(6-methyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (1.47 g) was prepared by following General Procedure Dstarting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g),2-amino-6-methyl-benzothiazole (0.82 g), 1,1′-thiocarbonyldiimidazole(1.07 g), and EDC (1.15 g). LC/MS: m/z 354.

Example 1151-Methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid methylamide

1-Methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid methylamide (27 mg) was prepared by following General Procedure Fusing1-methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benz-imidazole-5-carboxylicacid (41 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg),and DIEA (0.1 ml). LCMS: m/z 423.

Example 1161-Methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

1-Methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (35 mg) was prepared by following GeneralProcedure F using1-methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benz-imidazole-5-carboxylicacid (41 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1ml). LCMS: m/z 467.

Example 1172-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid

2-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (1.53 g) was prepared by following General Procedure E startingfrom2-(5-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid methyl ester (1.78 g), and LiOH (10.0 ml, 2.0 N solution in water).LC/MS: m/z 344.

Example 1182-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid

2-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (1.49 g) was prepared by following General Procedure E startingfrom2-(6-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid methyl ester (1.78 g), and LiOH (10.0 ml, 2.0 N solution in water).LC/MS: m/z 344.

Example 1192-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid

2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (1.75 g) was prepared by following General Procedure E startingfrom2-(6-methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid methyl ester (2.08 g), and LiOH (10.0 ml, 2.0 N solution in water).LC/MS: m/z 404.

Example 1201-Methyl-2-(6-methyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid

1-Methyl-2-(6-methyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (1.55 g) was prepared by following General Procedure E startingfrom1-methyl-2-(6-methyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid methyl ester (1.76 g), and LiOH (10.0 ml, 2.0 N solution in water).LC/MS: m/z 340.

Example 1211-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-yl)-amide (39 mg) was preparedby following General Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), 1,1-dioxo-tetrahydro-1λ⁶-thiophen-3-ylamine (30 mg), HBTU(38 mg), and DIEA (0.1 ml). LCMS: m/z 527; and ¹H NMR (DMSO-d₆, 400MHz): δ 8.72 (br, 1H), 8.09 (d, 1H), 7.92 (d, 1H), 7.78-7.63 (m, 2H),7.48 (d, 1H), 7.34 (d, 1H), 4.72 (m, 1H), 3.62 (s, 3H), 3.52 (m, 1H),3.38 (m, 1H), 3.20 (m, 1H), 3.08 (m, 1H), 2.43 (t, 2H), and 2.25 (m,1H).

Example 1222-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid methylamide

2-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid methylamide (24 mg) was prepared by following General Procedure Fusing2-(5-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (34 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg),and DIEA (0.1 ml). LCMS: m/z 357.

Example 1232-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

2-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (32 mg) was prepared by following GeneralProcedure F using2-(5-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (34 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1ml). LCMS: m/z 401; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.46 (t, 1H), 8.05(d, 1H), 7.95 (s, 1H), 7.79-7.71 (m, 2H), 7.42 (d, 1H), 7.30 (d, 1H),6.99 (t, 1H), 3.65 (s, 3H), 3.51-3.42 (m, 2H), 0.3.36 (d, 2H), and 2.73(s, 3H).

Example 1242-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid methylamide

2-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid methylamide (26 mg) was prepared by following General Procedure Fusing2-(6-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (34 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg),and DIEA (0.1 ml). LCMS: m/z 357. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.31 (m,1H), 7.93 (d, 1H), 7.63 (d, 2H), 7.50-7.42 (m, 1H), 7.38-7.28 (m, 1H),7.12 (t, 2H), 3.60 (s, 3H), and 2.78 (d, 3H).

Example 1252-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

2-(6-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (29 mg) was prepared by following GeneralProcedure F using2-(6-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (34 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1ml). LCMS: m/z 401; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.44 (m, 1H), 8.06(br, 1H), 7.76-7.70 (m, 2H), 7.66 (br, 1H), 7.45 (d, 1H), 7.20 (t, 1H),3.61 (s, 3H), 3.44 (m, 4H), and 3.26 (s, 3H), —NH proton signal was notobserved.

Example 1262-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid methylamide

2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid methylamide (34 mg) was prepared by following General Procedure Fusing2-(6-methanosulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (40 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg),and DIEA (0.1 ml). LCMS: m/z 417; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.45(m, 1H), 8.04 (br, 1H), 8.00 (m, 1H), 7.93 (s, 1H), 7.71 (t, 2H), 7.43(d, 1H), 7.18 (t, 1H), 3.63 (s, 3H), 3H), 3.27 (s, 3H), and 2.87 (s,3H).

Example 1272-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (33 mg) was prepared by following GeneralProcedure F using2-(6-methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benz-imidazole-5-carboxylicacid (40 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1ml). LCMS: m/z 461; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.36 (t, 1H), 8.14(br, 1H), 7.94 (d, 2H), 7.66 (d, 1H), 7.59 (d, 1H), 7.44 (d, 1H), 7.25(d, 1H), 3.61 (s, 3H), 3.45 (m, 4H), 3.27 (s, 3H), and 2.87 (s, 3H).

Example 1282-(6-Methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid methylamide

2-(6-Methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid methylamide (26 mg) was prepared by following General Procedure Fusing2-(6-methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (34 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg),and DIEA (0.1 ml). LCMS: m/z 353. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.32 (m,1H), 8.00 (br, 1H), 7.66 (d, 1H), 7.55 (s, 2H), 7.38 (m, 2H), 7.14 (d,1H), 3.63 (s, 3H), 2.87 (d, 3H), and 2.35 (s, 3H).

Example 1292-(6-Methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

2-(6-Methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (29 mg) was prepared by following GeneralProcedure F using2-(6-methyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (34 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1ml). LCMS: m/z 397.

Example 1302-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methylsulfanyl-ethyl)-amide

2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methylsulfanyl-ethyl)-amide (41 mg) was prepared by followingGeneral Procedure F using2-(6-methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (80 mg), 2-methylthio-ethylamine (0.2 ml), HBTU (76 mg), and DIEA(0.2 ml). LCMS: m/z 477.

Example 1312-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methylsulfonyl-ethyl)-amide

2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methylsulfonyl-ethyl)-amide (36 mg) was prepared by followingGeneral Procedure M using2-(6-methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (2-methylsulfanyl-ethyl)-amide (48 mg), and peracetic acid (0.1 ml,32 wt % solution in acetic acid). LC/MS: m/z 509. ¹H NMR (DMSO-d₆, 400MHz): δ 8.68 (m, 2H), 8.35 (s 1H), 8.08 (br, 1H), 7.93 (s, 1H), 7.84 (m,2H), 7.76 (br, 1H), 3.70 (m, 2H), 3.66 (s, 3H), 3.40 (t, 2H), 3.20 (s,3H), and 2.87 (d, 3H).

Example 1321-Methyl-2-(6-trifluoromethylsulfanyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester

4-Methylamino-3-nitro-benzoic acid methyl ester (822 mg) was prepared byfollowing General Procedure A starting from methyl4-chloro-3-nitrobenzoate (1.0 g) and methylamine (2.0 M in THF, 6.95 mL)in DMF (5 mL). The crude product was used in the next step withoutfurther purification.

3-amino-4-methylamino-benzoic acid methyl ester (677 mg) was prepared byfollowing General Procedure B starting from4-methylamino-3-nitro-benzoic acid methyl ester (822 mg) and Pd/C (10%by weight). The crude product was used in the next step without furtherpurification.

1-Methyl-2-(6-trifluoromethylsulfanyl-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid methyl ester (1.43 g) was prepared by following General Procedure Dstarting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g),6-trifluoromethylsulfanyl-benzothiazol-2-ylamine (1.25 g),1,1′-thiocarbonyldiimidazole (1.07 g), and EDC (1.15 g). LC/MS: m/z 440.¹H NMR (DMSO-d₆, 400 MHz): δ 8.23 (s, 2H), 7.89 (br, 1H), 7.76 (br, 1H),7.69 (d, 2H), 7.54 (d, 1H), 3.88 (s, 3H), and 3.68 (s, 3H).

Example 1332-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide (33 mg) was prepared by followingGeneral Procedure F using2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid (36 mg), 2-amino-N,N-dimethyl-acetamide acetic acid salt (48 mg),HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 444. ¹H NMR (DMSO-d₆, 400MHz): δ 11.70 (br, 1H), 8.44 (t, 1H), 8.11 (s, 1H), 7.94 (m, 1H), 7.80(m, 1H), 7.66 (br, 1H), 7.50 (d, 1H), 7.38 (d, 1H), 4.12 (d, 2H), 3.61(s, 3H), 3.03 (s, 3H), and 2.87 (s, 3H).

Example 1341-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide (38 mg) was prepared by followingGeneral Procedure F using1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (39 mg), 2-amino-N,N-dimethyl-acetamide acetic acid salt (48 mg),HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 478. ¹H NMR (DMSO-d₆, 400MHz): δ 12.49 (br, 1H), 8.46 (t, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.82(m, 2H), 7.68 (m, 1H), 7.53 (d, 1H), 4.13 (d, 2H), 3.66 (s, 3H), 3.04(s, 3H), and 2.87 (s, 3H).

Example 1351-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-dimethylcarbamoyl-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-dimethylcarbamoyl-ethyl)-amide (38 mg) was prepared by followingGeneral Procedure F using3-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionicacid (48 mg), dimethyl amine (0.3 ml, 1.0 M solution in THF), HBTU (38mg), and DIEA (0.1 ml). LC/MS: m/z 508. ¹H NMR (DMSO-d₆, 400 MHz): δ8.41 (t, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.73 (m, 2H), 7.46 (m, 1H),7.35 (d, 1H), 7.34 (m, 1H), 3.66 (s, 3H), 3.51-3.46 (q, 2H), 2.98 (s,3H), 2.84 (s, 3H), and 2.62 (t, 2H).

Example 1363-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionicacid tert-butyl ester

3-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionicacid tert-butyl ester (38 mg) was prepared by following GeneralProcedure F using1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (39 mg), β-alanine tert-butyl ester (42 mg), HBTU (38 mg), and DIEA(0.1 ml). LC/MS: m/z 537.

Example 1371-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide (41 mg) wasprepared by following General Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), 2-amino-1-(4-methyl-piperazin-1-yl)-ethanone (0.30 ml),HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 549. ¹H NMR (DMSO-d₆, 400MHz): δ 8.48 (t, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.91 (d, 1H), 7.78 (d,1H), 7.64 (br, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 4.14 (d, 2H), 3.67 (s,3H), 3.61 (m, 2H), 3.48 (m, 4H), 2.89 (s, 3H), and 2.32 (m, 2H).

Example 1381-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-morpholin-4-yl-2-oxo-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-morpholin-4-yl-2-oxo-ethyl)-amide (39 mg) was prepared byfollowing General Procedure F using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), 2-amino-1-morpholin-4-yl-ethanone (0.28 ml), HBTU (38 mg),and DIEA (0.1 ml). LC/MS: m/z 536. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.50 (t,1H), 8.10 (s, 1H), 7.92 (m, 1H), 7.79 (br, 1H), 7.74 (br, 1H), 7.50 (d,2H), 7.38 (m, 1H), 4.16 (d, 2H), 3.66 (s, 3H), 3.62 (m, 2H), 3.58 (t,2H), 3.52 (t, 2H), and 3.48 (t, 2H).

Example 1391-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid methylcarbamoylmethyl-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid methylcarbamoylmethyl-amide (47 mg) was prepared by followingGeneral Procedure F using{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-aceticacid (47 mg), methylamine (0.2 ml, 1.0 M solution in THF), HBTU (38 mg),and DIEA (0.1 ml), with a minor modification of General Procedure Fwhere DIEA was slowly added to the reaction mixture at last whilestirring at 0° C. LC/MS: m/z 480.

Example 1401-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid diethylcarbamoylmethyl-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid diethylcarbamoylmethyl-amide (48 mg) was prepared by followingGeneral Procedure F using{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-aceticacid (47 mg), diethylamine (0.2 ml), HBTU (38 mg), and DIEA (0.1 ml),with a minor modification of General Procedure F where DIEA was slowlyadded to the reaction mixture at last while stirring at 0° C. LC/MS: m/z522. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.45 (t, 1H), 8.08 (s, 1H), 7.90 (m,2H), 7.78 (br, 1H), 7.66 (br, 1H), 7.48 (d, 1H), 7.34 (d, 1H), 4.13 (d,2H), 3.66 (s, 3H), 3.38-3.28 (m, 4H), and 1.05 (t, 6H).

Example 1411-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-oxo-2-pyrrolidin-1-yl-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-oxo-2-pyrrolidin-1-yl-ethyl)-amide (46 mg) was prepared byfollowing General Procedure F using{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-aceticacid (47 mg), pyrrolidine (0.14 ml), HBTU (38 mg), and DIEA (0.1 ml),with a minor modification of General Procedure F where DIEA was slowlyadded to the reaction mixture at last while stirring at 0° C. LC/MS: m/z520. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.32 (t, 1H), 7.82 (s, 1H), 7.61 (m,2H), 7.52 (d, 1H), 7.28 (m, 1H), 7.17 (m, 1H), 7.09 (m, 1H), 4.02 (d,2H), 3.57 (s, 3H), 3.49 (t, 2H), 3.34 (m 2H), 1.91 (p, 2H), and 1.79 (p,2H).

Example 1424-(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetyl)-piperazine-1-carboxylicacid tert-butyl ester

4-(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetyl)-piperazine-1-carboxylicacid tert-butyl ester (58 mg) was prepared by following GeneralProcedure F using{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-aceticacid (47 mg), piperazine-1-carboxylic acid tert-butyl ester (34 mg),HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of GeneralProcedure F where DIEA was slowly added to the reaction mixture at lastwhile stirring at 0° C. LC/MS: m/z 635.

Example 143(S)-2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid methyl ester

(S)-2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid methyl ester (39 mg) was prepared by following General Procedure Fusing1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), L-alanine methyl ester hydrochloride (42 mg), HBTU (38mg), and DIEA (0.1 ml). LC/MS: m/z 495.

Example 1441-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-cyclopropanecarboxylicacid ethyl ester

1-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-cyclopropanecarboxylicacid ethyl ester (45 mg) was prepared by following General Procedure Fusing1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), 1-amino-cyclopropanecarboxylic acid ethyl esterhydrochloride (50 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 521.

Example 1452-Methyl-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionicacid methyl ester

2-Methyl-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionicacid methyl ester (43 mg) was prepared by following General Procedure Fusing1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (41 mg), 2-amino-2-methyl-propionic acid methyl ester hydrochloride(46 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 509.

Example 146(S)-2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid

(S)-2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carbonyl]-amino}-propionicacid (83 mg) was prepared by following General Procedure E starting from(S)-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid methyl ester (99 mg), and LiOH (0.5 ml, 2.0 N solution in water).LC/MS: m/z 481.

Example 1471-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-cyclopropanecarboxylicacid

1-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-cyclopropanecarboxylicacid (91 mg) was prepared by following General Procedure E starting from1-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-cyclopropanecarboxylicacid ethyl ester (104 mg), and LiOH (0.5 ml, 2.0 N solution in water).LC/MS: m/z 493.

Example 1482-Methyl-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionicacid

2-Methyl-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionicacid (88 mg) was prepared by following General Procedure E starting from2-methyl-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionicacid methyl ester (102 mg), and LiOH (0.5 ml, 2.0 N solution in water).LC/MS: m/z 495.

Example 1491-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-1-dimethylcarbamoyl-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-1-dimethylcarbamoyl-ethyl)-amide (46 mg) was prepared byfollowing General Procedure F using(S)-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionicacid (48 mg), dimethyl amine (0.3 ml, 1.0 M solution in THF), HBTU (38mg), and DIEA (0.1 ml), with a minor modification of General Procedure Fwhere DIEA was slowly added to the reaction mixture at last whilestirring at 0° C. LC/MS: m/z 508. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.39 (d,1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.76 (m, 1H), 7.66 (m, 1H), 7.45 (br,1H), 7.30 (m, 1H), 7.22 (d, 1H), 4.93 (p, 1H), 3.62 (s, 3H), 2.87 (d,6H), and 1.31 (d, 3H).

Example 1501-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (1-dimethylcarbamoyl-cyclopropyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (1-dimethylcarbamoyl-cyclopropyl)-amide (48 mg) was prepared byfollowing General Procedure F using1-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-cyclopropanecarboxylicacid (49 mg), dimethyl amine (0.3 ml, 1.0 M solution in THF), HBTU (38mg), and DIEA (0.1 ml), with a minor modification of General Procedure Fwhere DIEA was slowly added to the reaction mixture at last whilestirring at 0° C. LC/MS: m/z 520 [M+2]. ¹H NMR (DMSO-d₆, 400 MHz): δ8.92 (s, 1H), 8.06 (s, 1H), 7.91 (m, 1H), 7.72 (d, 1H), 7.60 (br, 1H),7.46 (d, 1H), 7.33 (d, 1H), 7.24 (m, 1H), 3.66 (s, 3H), 2.87 (d, 6H),1.26 (t, 2H), and 1.01 (t, 2H).

Example 1511-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (1-dimethylcarbamoyl-1-methyl-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (1-dimethylcarbamoyl-1-methyl-ethyl)-amide (47 mg) was prepared byfollowing General Procedure F using2-methyl-2-{[1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionicacid (49 mg), dimethyl amine (0.3 ml, 1.0 M solution in THF), HBTU (38mg), and DIEA (0.1 ml), with a minor modification of General Procedure Fwhere DIEA was slowly added to the reaction mixture at last whilestirring at 0° C. LC/MS: m/z 522. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.54 (s,1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.64 (br, 1H), 7.47 (d,1H), 7.36 (d, 1H), 3.67 (s, 3H), 2.87 (d, 6H), and 1.49 (s, 6H), —NHproton signals was not observed.

Example 1521-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide hydrochloride

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-oxo-2-piperazin-1-yl-ethyl)-amide dihydrochloride (42 mg) wasprepared by following General Procedure L using4-(2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-acetyl)-piperazine-1-carboxylicacid tert-butyl ester (63 mg), and hydrochloric acid (0.25 ml, 4.0 Nsolution dioxane). LC/MS: m/z 535. ¹H NMR (DMSO-d₆, 400 MHz): δ 9.55(br, 1H), 9.48 (br, 1H), 8.64 (t, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.84(d, 1H), 7.66 (d, 1H), 7.57 (d, 1H), 7.40 (d, 1H), 4.21 (d, 2H), 3.79(m, 2H), 3.73 (m, 2H), 3.71 (s, 3H), 3.16 (m, 2H), and 3.07 (m, 2H).

Example 1531-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester

4-Ethylamino-3-nitro-benzoic acid methyl ester (4.0 g) was prepared byfollowing General Procedure A starting from methyl4-chloro-3-nitrobenzoate (5.0 g) in ethylamine (2.0 M in THF, 50 mL).The crude product was used in the next step without furtherpurification.

3-Amino-4-ethylamino-benzoic acid methyl ester (3.2 g) was prepared byfollowing General Procedure B starting from 4-ethylamino-3-nitro-benzoicacid methyl ester (4.0 g) and Pd/C (20% by weight, 800.0 mg) inMeOH:EtOAc (1:1, 30.0 mL). The crude product was used in the next stepwithout further purification.

1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (3.70 g) was prepared by following General Procedure Dstarting from 3-amino-4-ethylamino-benzoic acid methyl ester (3.0 g),2-amino-6-(trifluoromethoxy)benzothiazole (4.4 g),1,1′-thiocarbonyldiimidazole (3.5 g), and EDC (3.6 g). LCMS: m/z 438;and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.25 and 8.05 (0.59 and 0.53, 1H, m),7.93 (2H, m), 7.75 (1H, m), 7.59 (1H, m), 7.38-7.37 (1H, m), 4.25-4.23(2H, m), 3.88 (3H, s), 1.35-1.31 (3H, t), —NH proton signal was notobserved.

Example 1541-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid

1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2.1 g) was prepared by following General Procedure E starting from1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (3.5 g) and sodium hydroxide (2.0 N solution, 8.0 mL).LCMS: m/z 424; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.17 (1H, m), 7.96 (1H,m), 7.75 (1H, m), 7.88-7.85 (1H, m), 7.65-7.63 (1H, m), 7.59-7.57 (1H,m), 7.40-7.37 (1H, m), 4.26-4.25 (2H, q), 1.35-1.32 (3H, t) —COOH protonsignal was not observed.

Example 1551-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide

1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide (50.0 mg) was prepared by following General Procedure Fstarting from1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), methylamine (2.0 M solution in THF, 1 mL), DPPA (82.0mg), and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 437; and ¹H NMR(CD₃OD, 400 MHz): δ 7.93 (1H, d), 7.73-7.70 (2H, m), 7.64-7.63 (1H, d),7.40-7.38 (1H, m), 7.25-7.22 (1H, m), 4.25-4.23 (2H, q), 2.95 (3H, s),1.41-1.38 (3H, t), 2 —NH proton signals were not observed.

Example 1561-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide

1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid ethylamide (53.0 mg) was prepared by following General Procedure Fstarting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (100.0 mg), ethylamine (2.0 M solution in THF, 1 mL), DPPA (85.0mg), and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 451; and ¹H NMR(CD₃OD, 400 MHz): δ 7.95 (1H, d), 7.75-7.73 (2H, m), 7.65-7.64 (1H, d),7.42-7.40 (1H, m), 7.26-7.24 (1H, m), 4.27-4.25 (2H, q), 3.47-3.42 (2H,q), 1.42-1.39 (3H, t), 1.27-1.24 (3H, t) 2 —NH proton signals were notobserved.

Example 1571-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide (60.0 mg) was prepared by following GeneralProcedure F starting from1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 2-ethoxy-ethylamine (30.0 mg), DPPA (85.0 mg), and DIEA(0.1 mL) in DMF (1.0 mL). LCMS: m/z 495; and ¹H NMR (CD₃OD, 400 MHz): δ7.96 (1H, d), 7.77-7.75 (2H, m), 7.65 (1H, d), 7.43-7.41 (1H, m),7.26-7.24 (1H, m), 4.27-4.26 (2H, q), 3.66-3.64 (2H, m), 3.59-3.55 (4H,m), 1.43-1.39 (3H, t), 1.23-1.20 (3H, t), 2 —NH proton signals were notobserved.

Example 158 1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1Hbenzoimidazole-5-carboxylic acid methyl ester

4-Isopropylamino-3-nitro-benzoic acid methyl ester (900.0 mg) wasprepared by following General Procedure A starting from methyl4-chloro-3-nitrobenzoate (1.0 g) and isopropyl amine (325.0 mg) in DMF(10.0 mL). The crude product was used in the next step without furtherpurification.

3-Amino-4-isopropylamino-benzoic acid methyl ester (700.0 mg) wasprepared by following General Procedure B starting from4-isopropylamino-3-nitro-benzoic acid methyl ester (900.0 mg) and Pd/C(20% by weight, 180.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crudeproduct was used in the next step without further purification.

1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (580.0 mg) was prepared by following General ProcedureD starting from 3-amino-4-isopropylamino-benzoic acid methyl ester(700.0 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (930.0 mg),1,1′-thiocarbonyldiimidazole (700.0 mg), and EDC (770.0 mg) in DMF (8.0mL). LCMS: m/z 452; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.27 and 8.05 (0.6and 0.47, 1H, m), 7.93 (1H, m), 7.84 (1H, m), 7.73 (2H, m), 7.37 (1H,m), 5.15 (1H, m), 3.88 (3H, s), 1.58-1.57 (6H, d), —NH proton signal wasnot observed.

Example 1591-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid

1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (500.0 mg) was prepared by following General Procedure E startingfrom1-isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (580.0 mg) and lithium hydroxide (2.0 N solution, 3.0mL), MeOH (2.0 mL) and THF (2.0 mL). LCMS: m/z 438; and ¹H NMR (DMSO-d₆,400 MHz): δ 8.17 (1H, m), 7.96 (1H, m), 7.84-7.82 (1H, m), 7.72-7.70(1H, m), 7.64-7.61 (1H, m), 7.40-7.37 (1H, m), 5.16-5.13 (1H, m),1.59-1.58 (6H, d), —NH proton and —COOH signals were not observed.

Example 1601-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide

1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide (44.0 mg) was prepared by following General Procedure Fstarting from1-isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (100.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU(130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 451; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.40 (1H, m), 8.10 (1H, m), 7.92 (1H, m),7.75-7.68 (2H, m), 7.37-7.35 (1H, m), 5.17-5.12 (1H, m), 2.82-2.80 (3H,s), 1.58-1.57 (6H, d), 2 —NH proton signals were not observed.

Example 1611-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide

1-Isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide (50.0 mg) was prepared by following General Procedure Fstarting from1-isopropyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (100.0 mg), ethylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 465; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.43 (1H, m), 8.11 (1H, m), 7.92 (1H, m),7.71-7.67 (2H, m), 7.36-7.35 (1H, m), 5.15-5.12 (1H, m), 3.32 (2H, m),1.58-1.57 (6H, d), 1.16-1.13 (3H, t), 2 —NH proton signals were notobserved.

Example 1621-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester

4-Isobutylamino-3-nitro-benzoic acid methyl ester (950.0 mg) wasprepared by following General Procedure A starting from methyl4-chloro-3-nitrobenzoate (1.0 g) and isobutyl amine (402.0 mg) in DMF(10.0 mL). The crude product was used in the next step without furtherpurification.

3-Amino-4-isobutylamino-benzoic acid methyl ester (790.0 mg) wasprepared by following General Procedure B starting from4-isobutylamino-3-nitro-benzoic acid methyl ester (950.0 mg) and Pd/C(20% by weight, 190.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crudeproduct was used in the next step without further purification.

1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (660.0 mg) was prepared by following General ProcedureD starting from 3-amino-4-isobutylamino-benzoic acid methyl ester (790.0g), 2-amino-6-(trifluoromethoxy)benzothiazole (930.0 mg),1,1′-thiocarbonyldiimidazole (700.0 mg), and EDC (770.0 mg) in DMF (8.0mL). LCMS: m/z 466; and ¹H NMR (DMSO-d₆, 400 MHz): δ 8.25 and 8.05 (0.6and 0.46, 1H, m), 7.98-7.88 (2H, m), 7.75-7.73 (1H, m), 7.60-7.58 (1H,m), 7.38-7.37 (1H, m), 4.00-3.98 (2H, m), 3.88 (3H, s), 2.29-2.28 (1H,m), 0.92-0.86 (6H, m), —NH proton signal was not observed.

Example 1631-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid

1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (570.0 mg) was prepared by following General Procedure E startingfrom1-isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (660.0 mg) and lithium hydroxide (2.0 N solution, 3.0mL) MeOH (1.0 mL) and THF (3.0 mL). LCMS: m/z 452; and ¹H NMR (DMSO-d₆,400 MHz): δ 8.16 (1H, m), 7.97-7.94 (1H, m), 7.85-7.82 (1H, m),7.57-7.55 (2H, m), 7.39-7.37 (1H, m), 4.03-4.01 (2H, d), 2.29-2.24 (1H,m), 0.93-0.91 (6H, d), 2 —NH proton signals were not observed.

Example 1641-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide

1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide (40.0 mg) was prepared by following General Procedure Fstarting from1-isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (100.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU(130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 465; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.40 (1H, m), 8.09 (1H, m), 7.91 (1H, m), 7.72(1H, m), 7.54 (1H, m), 7.35 (1H, m), 4.00-3.99 (2H, m), 2.81-2.80 (3H,d), 1.23 (1H, m), 0.95-0.92 (6H, m), 2 —NH proton signals were notobserved.

Example 1651-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide

1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide (47.0 mg) was prepared by following General Procedure Fstarting from1-isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (100.0 mg), ethylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 479 and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.43 (1H, m), 8.09 (1H, m), 7.91 (1H, m), 7.73(1H, m), 7.54 (1H, m), 7.37-7.35 (1H, m), 4.04-4.00 (2H, m), 3.32 (2H,m), 2.28 (1H, m), 1.16-1.13 (3H, t), 0.95-0.91 (6H, m), 2 —NH protonsignals were not observed.

Example 1661-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid

4-(2-Methoxy-ethylamino)-3-nitro-benzoic acid methyl ester (960.0 mg)was prepared by following General Procedure A starting from methyl4-chloro-3-nitrobenzoate (1.0 g) and 2-methoxy-ethylamine (413.0 mg) inDMF (10.0 mL). The crude product was used in the next step withoutfurther purification.

3-Amino-4-(2-methoxy-ethylamino)-benzoic acid methyl ester (800.0 mg)was prepared by following General Procedure B starting from4-(2-methoxy-ethylamino)-3-nitro-benzoic acid methyl ester (960.0 mg)and Pd/C (20% by weight, 190.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). Thecrude product was used in the next step without further purification.

1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (829.0 mg) was prepared by following General ProcedureD starting from 3-amino-4-(2-methoxy-ethylamino)-benzoic acid methylester (800.0 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (930.0 mg),1,1′-thiocarbonyldiimidazole (700.0 mg), and EDC (770.0 mg) in DMF (8.0mL).

1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (723.0 mg) was prepared by following General Procedure E startingfrom1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (829.0 mg) and sodium hydroxide (2.0 N solution, 3.0mL) MeOH (1.0 mL) and THF (3.0 mL). LCMS: m/z 454; and ¹H NMR (DMSO-d₆,400 MHz): δ 8.14 (1H, s), 7.95 (1H, m), 7.84-7.82 (1H, m), 7.63 (1H, br.m), 7.51 (1H, m), 7.55-7.52 (1H, m), 7.39-7.36 (1H, m), 4.39-4.36 (2H,t), 3.74-3.71 (2H, t), 3.24 (3H, s), —COOH proton signal was notobserved.

Example 1671-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide

1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide (46.0 mg) was prepared by following General Procedure Fstarting from1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU(130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 467; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.39 (1H, br. s), 8.07 (1H, br. s), 7.92 (1H, br.s), 7.74-7.72 (1H, br. m), 7.51-7.49 (1H, m), 7.37-7.35 (1H, m), 4.35(4H, br. s), 3.73-3.72 (2H, br. t), 3.24 (3H, s), 2.82-2.80 (3H, d).

Example 1681-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (42.0 mg) was prepared by following GeneralProcedure F starting from1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 2-methoxy-ethylamine (26.0 mg), HBTU (130.0 mg) andDIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 511; and ¹H NMR (DMSO-d₆, 400MHz): δ 8.47 (1H, br. s), 8.08 (1H, br. s), 7.93 (1H, br. s), 7.74-7.72(1H, br. m), 7.51 (1H, m), 7.37-7.35 (1H, m), 4.35 (2H, br. s),3.73-3.72 (2H, br. t), 3.53-3.43 (4H, m), 3.29 (3H, s), 3.24 (3H, s), 2—NH proton signals were not observed.

Example 1691-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide (49.0 mg) was prepared by following GeneralProcedure F starting from1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 2-ethoxy-ethylamine (30.0 mg), HBTU (130.0 mg) and DIEA(0.1 mL) in DMF (1.0 mL). LCMS: m/z 525; and ¹H NMR (DMSO-d₆, 400 MHz):δ 8.44 (1H, br. s), 8.06 (1H, br. s), 7.91 (1H, br. s), 7.71 (1H, br.m), 7.49-7.47 (1H, m), 7.35-7.34 (1H, m), 4.34 (2H, br. s), 3.72-3.69(2H, br. t), 3.52-3.40 (6H, m), 3.22 (3H, s), 1.13-1.09 (3H, t), 2 —NHproton signals were not observed.

Example 1701-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide

4-(2-Fluoro-ethylamino)-3-nitro-benzoic acid methyl ester (854.0 mg) wasprepared by following General Procedure A starting from methyl4-chloro-3-nitrobenzoate (1.0 g), DIEA (2.0 mL) and 2-fluoro-ethylamine(335.0 mg) in DMF (10.0 mL). The crude product was used in the next stepwithout further purification.

3-Amino-4-(2-fluoro-ethylamino)-benzoic acid methyl ester (657.0 mg) wasprepared by following General Procedure B starting from4-(2-fluoro-ethylamino)-3-nitro-benzoic acid methyl ester (854.0 mg) andPd/C (20% by weight, 170.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crudeproduct was used in the next step without further purification.

1-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (550.0 mg) was prepared by following General ProcedureD starting from 3-amino-4-(2-fluoro-ethylamino)-benzoic acid methylester (657.0 mg), 2-amino-6-(trifluoromethoxy)benzothiazole (819.0 mg),1,1′-thiocarbonyldiimidazole (623.0 mg), and EDC (670.0 mg) in DMF (6.0mL).

1-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (475.0 mg) was prepared by following General Procedure E startingfrom1-(2-fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (550.0 mg) and sodium hydroxide (2.0 N solution, 3.0mL) MeOH (1.0 mL) and THF (3.0 mL). LCMS: m/z 441 (M+2)⁺ and ¹H NMR(CD₃OD, 400 MHz): δ 8.16 (1H, m), 8.06-8.03 (1H, m), 7.96 (1H, m),7.86-7.84 (1H, m), 7.57-7.52 (1H, m), 7.44-7.37 (2H, m), 4.89-4.75 (2H,m), 4.59-4.51 (2H, m) (—COOH proton signal was not observed).

1-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide (39.0 mg) was prepared by following General Procedure Fstarting from1-(2-fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU(130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 455; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.35-8.34 (1H, m), 8.13-8.08 (1H, m), 8.02-8.01(1H, m), 7.90-7.80 (1H, m), 7.74-7.68 (1H, m), 7.51-7.36 (2H, m),4.87-4.83 (1H, m), 4.51-4.45 (1H, m), 3.30 (3H, s), 2.80-2.79 (2H, d),—NH proton signal was not observed.

Example 1711-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

1-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (49.0 mg) was prepared by following GeneralProcedure F starting from1-(2-fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 2-methoxy-ethylamine (26.0 mg), HBTU (130.0 mg) andDIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 499.

Example 1721-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

1-(2-Fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide (50.0 mg) was prepared by following GeneralProcedure F starting from1-(2-fluoro-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 2-ethoxy-ethylamine (31.0 mg), HBTU (130.0 mg) and DIEA(0.1 mL) in DMF (1.0 mL). LCMS: m/z 513.

Example 1731-(2-Amino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide hydrochloride

4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-benzoic acid methylester (650.0 mg) was prepared by following General Procedure A startingfrom methyl 4-chloro-3-nitrobenzoate (542.0 mg) and(2-amino-ethyl)-carbamic acid tert-butyl ester (500.0 mg) in DMF (3.0mL). The crude product was used in the next step without furtherpurification.

3-Amino-4-(2-tert-butoxycarbonylamino-ethylamino)-benzoic acid methylester (525.0 mg) was prepared by following General Procedure B startingfrom 4-(2-tert-butoxycarbonylamino-ethylamino)-3-nitro-benzoic acidmethyl ester (650.0 mg) and Pd/C (20% by weight, 130.0 mg) in MeOH:EtOAc(1:1, 6.0 mL). The crude product was used in the next step withoutfurther purification.

1-(2-tert-Butoxycarbonylamino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (374.0 mg) was prepared by following General ProcedureD starting from3-amino-4-(2-tert-butoxycarbonylamino-ethylamino)-benzoic acid methylester (525.0 mg), 2-amino-6-(trifluoromethoxy)-benzothiazole (585.0 mg),1,1′-thiocarbonyldiimidazole (445.0 mg), and EDC (480.0 mg) in DMF (2.0mL).

1-(2-tert-Butoxycarbonylamino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (327.0 mg) was prepared by following General Procedure E startingfrom1-(2-tert-butoxycarbonylamino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (374.0 mg) and sodium hydroxide (2.0 N solution, 1.0mL) MeOH (0.5 mL) and THF (2.0 mL).

{2-[5-Methylcarbamoyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-benzoimidazol-1-yl]-ethyl}-carbamicacid tert-butyl ester (39.0 mg) was prepared by following GeneralProcedure F starting from1-(2-tert-butoxycarbonylamino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75.0 mg), methylamine (2.0 M solution in THF, 0.5 mL), HBTU (80.0mg) and DIEA (0.05 mL) in DMF (1.0 mL).

1-(2-Amino-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylicacid methylamide hydrochloride (16.0 mg) was prepared using 4.0 MHCl-dioxane:DCM (2:1, 1.0 mL). LCMS: m/z 452; and ¹H NMR (CD₃OD, 400MHz): δ 8.35-8.34 (1H, m), 8.06-8.05 (1H, m), 7.89-7.62 (5H, m),7.42-7.37 (2H, m), 4.63-4.60 (2H, m), 3.50 (1H, m), 2.98-2.96 (3H, d),2.89-2.85 (2H, m).

Example 1742-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid methylamide

4-Ethylamino-3-nitro-benzoic acid methyl ester (8.3 g) was prepared byfollowing General Procedure A starting from methyl4-chloro-3-nitrobenzoate (10.0 g), DIEA (1.6 mL) and ethylaminehydrochloride salt (4.5 g) in DMF (50.0 mL). The crude product was usedin the next step without further purification.

3-Amino-4-ethylamino-benzoic acid methyl ester (6.4 g) was prepared byfollowing General Procedure B starting from 4-ethylamino-3-nitro-benzoicacid methyl ester (8.3 g) and Pd/C (20% by weight, 170 mg) in MeOH:EtOAc(1:1, 50.0 mL). The crude product was used in the next step withoutfurther purification.

2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid methyl ester (926.0 mg) was prepared by following General ProcedureD starting from 3-amino-4-ethylamino-benzoic acid methyl ester (1.06 g),2-amino-6-chloro-benzothiazole (1.0 g), 1,1′-thiocarbonyldiimidazole(979.0 mg), and EDC (1.05 g) in DMF (5.0 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (803.0 mg) was prepared by following General Procedure E startingfrom2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid methyl ester (926.0 mg) and sodium hydroxide (2.0 N solution, 2.0mL) MeOH (1.0 mL) and THF (2.0 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid methylamide (77.0 mg) was prepared by following General Procedure Fstarting from2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (150.0 mg), methylamine (2.0 M solution in THF, 1.0 mL), HBTU (190mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 387; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.40 (1H, br. s), 8.08 (1H, br. s), 7.95 (1H, m),7.73 (2H, m), 7.51 (1H, m), 7.41-7.38 (1H, m), 4.21 (1H, bs. s),2.82-2.80 (3H, d), 1.34-1.30 (3H, t), 2 —NH proton signals were notobserved.

Example 1752-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid ethylamide

2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid ethylamide (70.0 mg) was prepared by following General Procedure Fstarting from2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (150.0 mg), ethylamine (2.0 M solution in THF, 1.0 mL), HBTU (190.0mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 401; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.44 (1H, m), 8.08 (1H, m), 7.95-7.92 (1H, m),7.75-7.64 (2H, m), 7.53-7.51 (1H, m), 7.41-7.38 (1H, m), 4.21-4.19 (2H,m), 3.32-3.28 (2H, m), 1.34-1.32 (3H, t), 1.17-1.13 (3H, t), —NH protonsignal was not observed.

Example 1762-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (2-fluoro-ethyl)-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (2-fluoro-ethyl)-amide (75.0 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (150.0 mg), 2-fluoro-ethylamine (38.0 mg), HBTU (190.0 mg) and DIEA(0.2 mL) in DMF (1.0 mL). LCMS: m/z 419⁺.

Example 1772-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (68.0 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (150.0 mg), 2-methoxy-ethylamine (45.0 mg), HBTU (190.0 mg) andDIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 431; and ¹H NMR (DMSO-d₆, 400MHz): δ 8.46 (1H, br. s), 8.08 (1H, br. s), 7.92 (1H, br. s), 7.76-7.65(2H, m), 7.51 (1H, m), 7.40-7.38 (1H, m), 4.22 (2H, br. s), 3.50-3.43(4H, m), 3.29 (3H, s), 1.33-1.30 (3H, t), —NH proton signal was notobserved.

Example 1782-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (2-methoxy-2-methyl-propyl)-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (2-methoxy-2-methyl-propyl)-amide (73.0 mg) was prepared byfollowing General Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzo-imidazole-5-carboxylicacid (150.0 mg), 2-methoxy-2-methyl-propylamine (61.0 mg), HBTU (190.0mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 459; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.18-8.16 (1H, m), 8.08 (1H, m), 7.92-7.91 (1H,m), 7.79-7.77 (1H, m), 7.67-7.65 (1H, m), 7.54-7.52 (1H, m), 7.40-7.37(1H, m), 4.21-4.20 (2H, m), 3.37-3.35 (2H, d), 3.18 (3H, s), 1.34-1.30(3H, t), 1.14 (6H, s), —NH proton signal was not observed.

Example 1792-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide (79.0 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (150.0 mg), 2-ethoxy-ethylamine (53.0 mg), HBTU (190.0 mg) and DIEA(0.2 mL) in DMF (1.0 mL). LCMS: m/z 445; and ¹H NMR (DMSO-d₆, 400 MHz):δ 8.47 (1H, br. s), 8.08 (1H, br. s), 7.92 (1H, br. s), 7.76-7.63 (2H,m), 7.52 (1H, m), 7.40-7.38 (1H, m), 4.22 (2H, m), 3.53-3.41 (6H, m),1.34-1.30 (3H, t), 1.14-1.11 (3H, t), —NH proton signal was notobserved.

Example 1801-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide

4-Ethylamino-3-nitro-benzoic acid methyl ester (8.3 g) was prepared byfollowing General Procedure A starting from methyl4-chloro-3-nitrobenzoate (10.0 g), DIEA (1.6 mL) and ethylaminehydrochloride salt (4.5 g) in DMF (50.0 mL). The crude product was usedin the next step without further purification.

3-Amino-4-ethylamino-benzoic acid methyl ester (6.4 g) was prepared byfollowing General Procedure B starting from 4-ethylamino-3-nitro-benzoicacid methyl ester (8.3 g) and Pd/C (20% by weight, 170 mg) in MeOH:EtOAc(1:1, 50.0 mL). The crude product was used in the next step withoutfurther purification.

1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (840.0 mg) was prepared by following General ProcedureD starting from 3-amino-4-ethylamino-benzoic acid methyl ester (970.0mg), 6-trifluoromethyl-benzothiazol-2-ylamine (1.0 g),1,1′-thiocarbonyldiimidazole (890.0 mg), and EDC (970.0 mg) in DMF (5.0mL).

1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (770.0 mg) was prepared by following General Procedure E startingfrom1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (840.0 mg) and sodium hydroxide (2.0 N solution, 2.0mL) MeOH (1.0 mL) and THF (2.0 mL).

1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylamide (75.0 mg) was prepared by following General Procedure Fstarting from1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (150.0 mg), methylamine (2.0 M solution in THF, 1.0 mL), HBTU(200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 421.

Example 1811-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide

1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide (70.0 mg) was prepared by following General Procedure Fstarting from1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (150.0 mg), ethylamine (2.0 M solution in THF, 1.0 mL), HBTU (200.0mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 435; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.45-8.39 (1H, m), 8.29-8.25 (1H, m), 8.12-8.08(1H, m), 7.82-7.67 (3H, m), 7.57-7.50 (1H, m), 4.26-4.22 (2H, m),3.31-3.29 (2H, m), 1.35-1.32 (3H, t), 1.17-1.13 (3H, t), —NH protonsignal was not observed.

Example 1821-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (64.0 mg) was prepared by following GeneralProcedure F starting from1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (150.0 mg), 2-methoxy-ethylamine (38.0 mg), HBTU (200.0 mg) andDIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 465; and ¹H NMR (DMSO-d₆, 400MHz): δ 8.50 (1H, m), 8.25 (1H, br. s), 8.12 (1H, br., s), 7.82-7.78(2H, m), 7.70-7.68 (1H, m), 7.57-7.54 (1H, m), 4.24 (2H, m), 3.51-3.43(4H, m), 3.29 (3H, s), 1.35-1.31 (3H, t), —NH proton signal was notobserved.

Example 1831-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide

1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide (66.0 mg) was prepared by following GeneralProcedure F starting from1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (150.0 mg), 2-ethoxy-ethylamine (45.0 mg), HBTU (200.0 mg) and DIEA(0.2 mL) in DMF (1.0 mL). LCMS: m/z 479.

Example 1841-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-2-methyl-propyl)-amide

1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-2-methyl-propyl)-amide (78.0 mg) was prepared byfollowing General Procedure F starting from1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (150.0 mg), 2-methoxy-2-methyl-propylamine (50.0 mg), HBTU (200.0mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 493; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.25 (1H, br. s), 8.20-8.17 (1H, m), 8.11 (1H,br., s), 7.81 (1H, m), 7.70 (1H, m), 7.57 (1H, m), 4.25 (2H, m),3.37-3.35 (2H, d), 3.32 (2H, s), 3.18 (3H, s), 1.35-1.32 (3H, t), 1.14(6H. s).

Example 1851-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methylsulfanyl-ethyl)-amide

1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methylsulfanyl-ethyl)-amide (67.0 mg) was prepared by followingGeneral Procedure F starting from1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (150.0 mg), 2-methylsulfanyl-ethylamine (45.0 mg), HBTU (200.0 mg)and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 481; and ¹H NMR (DMSO-d₆,400 MHz): δ 8.59 (1H, br. s), 8.26 (1H, br. s), 8.11 (1H, br., s),7.76-7.68 (2H, m), 7.56 (1H, m), 4.25 (2H, bs. s), 3.51-3.46 (2H, q),3.32 (2H, s), 2.70-2.66 (2H, t), 2.12 (3H, s), 1.35-1.32 (3H, t).

Example 1861-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide

1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide (45.0 mg) was prepared by followingGeneral Procedure F starting from1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 2-amino-N,N-dimethyl-acetamide (25.0 mg), HBTU (190.0mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 508; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.19 (1H, br. s), 7.88 (1H, br. s), 7.68 (1H, br.,s), 7.55 (1H, br., s), 7.34-7.24 (2H, m), 7.13 (1H, m), 4.19-4.16 (2H,m), 4.12-4.10 (2H, d), 3.03 (3H, s), 2.88 (3H, s), 1.31-1.27 (3H, t),—NH proton signal was not observed.

Example 1871-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide

1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide (40.0 mg) was prepared by followingGeneral Procedure F starting from1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 2-amino-N,N-dimethyl-acetamide (25.0 mg), HBTU (190.0mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 492; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.25 (1H, m), 7.88-7.84 (2H, m), 7.51-7.49 (1H,m), 7.37-7.28 (2H, m), 7.19-7.18 (1H, m), 4.18-4.15 (2H, m), 4.11-4.09(2H, m), 3.03 (3H, s), 2.87 (3H, s), 1.29-1.23 (3H, t), —NH protonsignal was not observed.

Example 1881-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide

1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide (35.0 mg) was prepared by followingGeneral Procedure F starting from1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 2-amino-N,N-dimethyl-acetamide (25.0 mg), HBTU (190.0mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 537.6; and ¹H NMR(DMSO-d₆, 400 MHz): δ 8.59 (1H, m), 7.90 (1H, br. s), 7.72 (1H, br., s),7.56-7.54 (1H, m), 7.38-7.31 (2H, m), 7.18 (1H, m), 4.30-4.27 (2H, t),4.11-4.10 (2H, d), 3.70-3.67 (2H, t), 3.25 (3H, s), 3.03 (3H, s), 2.87(3H, s), —NH proton signal was not observed.

Example 1891-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide

1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide (45.0 mg) wasprepared by following General Procedure F starting from1-(2-methoxy-ethyl)₂-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 2-amino-1-(4-methyl-piperazin-1-yl)-ethanone (40.0 mg),HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 593; and ¹HNMR (DMSO-d₆, 400 MHz): δ 8.49-8.46 (1H, m), 8.09 (1H, br. s), 7.95-7.93(2H, m), 7.74 (1H, m), 7.53-7.50 (1H, m), 7.37-7.34 (1H, m), 4.37-4.36(2H, m), 4.16-4.14 (2H, d), 3.74-3.71 (2H, t), 3.48-3.46 (4H, m), 3.24(3H, s), 2.36-2.28 (4H, m), 2.20 (3H, s), —NH proton signal was notobserved.

Example 1901-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide

1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide (50.0 mg) wasprepared by following General Procedure F starting from1-ethyl-2-(6-trifluoromethoxybenzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 2-amino-1-(4-methyl-piperazin-1-yl)-ethanone (40.0 mg),HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 563; and ¹HNMR (DMSO-d₆, 400 MHz): δ 8.51-8.48 (1H, m), 8.12 (1H, br. s), 7.93 (1H,br., s), 7.74-7.71 (2H, m), 7.55 (1H, m), 7.37 (1H, m), 4.26 (2H, bs.s), 4.16-4.15 (2H, m), 3.51-3.50 (4H, m), 2.40-2.33 (4H, m), 2.24 (3H,s), 1.35-1.31 (3H, t), —NH proton signal was not observed.

Example 1911-Ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide

6-(Pyridin-3-yloxy)-benzothiazol-2-ylamine (2.1 g) was prepared using4-(pyridin-3-yloxy)-phenylamine (2.0 g) and KCNS (3.3 g) in acetic acid(45.0 ml). The reaction was stirred at room temperature for 20 min.Bromine (0.3 mL) in 3.0 ml acetic acid was added slowly and the reactionwas stirred at room temperature for 8-10 h. The reaction mixture wasdiluted with water (100.0 ml), and the precipitate was filtered anddried. The precipitate was washed with saturated sodium bicarbonatesolution and the crude product was used in the next step without furtherpurification.

1-Ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylicacid methyl ester (155.0 mg) was prepared by following General ProcedureD starting from 3-amino-4-ethylamino-benzoic acid methyl ester (160.0mg), 6-(pyridin-3-yloxy)-benzothiazol-2-ylamine (200.0 mg),1,1′-thiocarbonyldiimidazole (200.0 mg), and EDC (200.0 mg) in DMF (2.0mL).

1-Ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylicacid (133.0 mg) was prepared by following General Procedure E startingfrom1-ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylicacid methyl ester (155.0 mg) and sodium hydroxide (2.0 N solution, 1.0mL) MeOH (0.5 mL) and THF (1.0 mL).

1-Ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide (61.0 mg) was prepared by following GeneralProcedure F starting from1-ethyl-2-[6-(pyridin-3-yloxy)-benzothiazol-2-ylamino]-1H-benzoimidazole-5-carboxylicacid (133.0 mg), 2-methoxy-ethylamine (38.0 mg), HBTU (200.0 mg) andDIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 490. ¹H NMR (DMSO-d₆, 400 MHz):δ 8.44 (1H, m), 8.38-8.32 (2H, m), 8.07 (1H, m), 7.76-7.68 (2H, m),7.51-7.45 (1H, m), 7.40-7.39 (2H, m), 7.12-7.10 (1H, m), 4.20-4.17 (2H,m), 3.48-3.42 (3H, m), 3.26 (3H, s), 1.48-1.46 (1H, m), 1.32-1.28 (3H,t), 2 —NH proton signals were not observed.

Example 1921-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-hydroxy-piperidin-1-yl)-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-hydroxy-piperidin-1-yl)-ethyl]-amide (50.0 mg) was preparedby following General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 1-(2-amino-ethyl)-piperidin-4-ol (72.0 mg), HBTU (200.0mg) and DIEA (0.2 mL) in DMF (1.0 mL).

LCMS: m/z 421. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.00 (1H, m), 7.80-7.77 (1H,m), 7.65 (1H, m), 7.41-7.39 (1H, m), 7.26-7.24 (1H, m), 3.90 (1H, m),3.75-3.72 (2H, t), 3.69 (3H, s), 3.37 (1H, m), 3.18 (2H, m), 2.07-2.02(2H, m), 1.83-1.78 (2H, m), 1.32-1.29 (2H, m), 0.90-0.87 (2H, m), 2 —NHand —OH proton signals were not observed.

Example 1931-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(3-hydroxy-piperidin-1-yl)-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(3-hydroxy-piperidin-1-yl)-ethyl]-amide (38.0 mg) was preparedby following General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100.0 mg), 1-(2-amino-ethyl)-piperidin-3-ol (72.0 mg), HBTU (200.0mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 536. ¹H NMR (DMSO-d₆,400 MHz): δ 7.90 (1H, m), 7.72-7.65 (2H, m), 7.61 (1H, m), 7.33-7.30(1H, m), 7.23-7.21 (1H, m), 3.78-3.74 (1H, m), 3.64 (3H, s), 3.60-3.56(2H, t), 2.99-2.96 (1H, m), 2.81-2.78 (1H, m), 2.72-2.69 (2H, t),2.30-2.22 (2H, m), 1.92-1.83 (2H, m), 1.63-1.58 (1H, m), 1.37-1.34 (1H,m), 2 —NH and —OH proton signals were not observed.

Example 1941-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonitrile

4-Methylamino-3-nitro-benzonitrile (1.69 mg) was prepared by followingGeneral Procedure A starting from methyl 4-fluoro-3-nitrobenzonitrile(1.66 g) and methylamine (2 M in THF, 10.0 mL) in DMF. The crude productwas used in the next step without further purification.

3-Amino-4-methylamino-benzonitrile (1.23 mg) was prepared by followingGeneral Procedure B starting from 4-methylamino-3-nitro-benzonitrile(1.33 g) and Pd/C (10% by weight, 133 mg). The crude product was used inthe next step without further purification.

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonitrile(2.12 g) was prepared by following General Procedure D starting from3-amino-4-methylamino-benzonitrile (1.1 g),2-amino-6-(trifluoromethoxy)-benzothiazole (1.75 g),1,1′-thiocarbonyldiimidazole (1.78 g), and EDC (1.9 g). LC/MS: m/z 391.¹H NMR (DMSO-d₆, 400 MHz): δ 7.97 (s, 1H), 7.89 (s, 1H), 7.78 (br, 1H),7.60 (d, 2H), 7.55 (br, 1H), 7.39 (d, 1H), and 3.72 (s, 3H).

Example 1951-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-6-carbonitrile

3-Methylamino-4-nitro-benzonitrile (1.58 mg) was prepared by followingGeneral Procedure A starting from methyl 3-fluoro-4-nitrobenzonitrile(1.66 g) and methylamine (2 M in THF, 10.0 mL) in DMF. The crude productwas used in the next step without further purification.

4-Amino-3-methylamino-benzonitrile (1.17 mg) was prepared by followingGeneral Procedure B starting from 3-methylamino-4-nitro-benzonitrile(1.33 g) and Pd/C (10% by weight, 133 mg). The crude product was used inthe next step without further purification.

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-6-carbonitrile(2.27 g) was prepared by following General Procedure D starting from4-amino-3-methylamino-benzonitrile (1.1 g),2-amino-6-(trifluoromethoxy)-benzothiazole (1.75 g),1,1′-thiocarbonyldiimidazole (1.78 g), and EDC (1.9 g). LC/MS: m/z 391.

Example 196[5-(1H-Imidazol-2-yl)-1-methyl-1H-benzimidazol-2-yl]-(6-trifluoromethoxy-benzothiazol-2-yl)-amine

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonitrile(2.27 g) was prepared by following General Procedure D starting from4-amino-3-methylamino-benzonitrile (1.1 g),2-amino-6-(trifluoromethoxy)benzothiazole (1.75 g),1,1′-thiocarbonyldiimidazole (1.78 g), and EDC (1.9 g). This product wastriturated with DCM-methanol (9:1) before being used in the next step.

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboximidicacid ethyl ester (630 mg) was prepared from1-methyl-2-(6-trifluoro-methoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonitrile(778 mg) and aminoacetaldehyde diethylacetal (0.53 ml) and AcOH (0.6 ml)by following Step 1 of General Procedure I. The crude product was usedin the next step without further purification.

[5-(1H-Imidazol-2-yl)-1-methyl-1H-benzimidazol-2-yl]-(6-trifluoromethoxy-benzothiazol-2-yl)-amine(316 mg) was prepared by following Step 2 of General Procedure Istarting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboximidicacid ethyl ester (435 mg), AcOH (0.5 ml), and dilute hydrochloric acid(5.0 ml, 1.0 N solution in water). LC/MS: m/z 432.

Example 197[1-Methyl-6-(1H-1,2,4-triazol-3-yl)-1H-benzimidazol-2-yl]-(6-trifluoromethoxy-benzothiazol-2-yl)-amine

[1-Methyl-6-(1H-1,2,4-triazol-3-yl)-1H-benzimidazol-2-yl]-(6-trifluoromethoxy-benzothiazol-2-yl)-amine(106 mg) was prepared by following Method B of General Procedure J using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benz-imidazole-5-carboximidicacid ethyl ester (218 mg) and formic hydrazide (18 mg). LC/MS: m/z 433.¹H NMR (DMSO-d₆, 400 MHz): δ 9.06 (br, 1H), 8.12 (s, 1H), 7.99 (m, 2H),7.88 (d, 2H), 7.46 (d, 1H), 4.48 (br, 1H), and 3.63 (s, 3H), —NH protonsignal was not observed.

Example 198[1-Methyl-6-(5-methyl-1H-1,2,4-triazol-3-yl)-1H-benzimidazol-2-yl]-(5-trifluoromethoxy-benzothiazol-2-yl)-amine

[1-Methyl-6-(5-methyl-1H-1,2,4-triazol-3-yl)-1H-benzimidazol-2-yl]-(5-trifluoromethoxy-benzothiazol-2-yl)-amine(112 mg) was prepared by following Method B of General Procedure J using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboximidicacid ethyl ester (218 mg) and acetic hydrazide (18 mg). LC/MS: m/z 447.¹H NMR (DMSO-d₆, 400 MHz): δ 9.86 (br, 1H), 9.65 (s, 2H), 9.05 (br, 1H),8.92 (m, 1H), 7.99 (d, 1H), 7.88 (s, 2H), 3.42 (s, 3H), and 1.81 (s,3H).

Example 199(1-Ethyl-5-trifluoromethanesulfonyl-1H-benzoimidazol-2-yl)-(6-trifluoromethoxy-benzothiazol-2-yl)-amine

(1-Ethyl-5-trifluoromethanesulfonyl-1H-benzoimidazol-2-yl)-(6-trifluoromethoxy-benzothiazol-2-yl)-amine(399 mg) was prepared by following General Procedure D usingN¹-ethyl-4-trifluoromethanesulfonyl-benzene-1,2-diamine (187 mg),6-trifluoro-methoxy-2-amino-benzothiazole (234 mg),1,1′-thiocarbonyl-diimidazole (213 mg), and EDC (287 mg). LC/MS: m/z512. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.12 (br, 1H), 7.98 (s, 1H), 7.88 (m,1H), 7.85 (s, 1H), 7.46 (br, 1H), 7.40 (d, 2H), 4.12 (q, 2H), and 1.34(t, 3H).

Example 2001-[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazol-5-yl]-ethanone

1-(4-Methylamino-3-nitro-phenyl)-ethanone (153 mg) was prepared byfollowing General Procedure A starting from methyl1-(4-fluoro-3-nitro-phenyl)-ethanone (183 mg) and methylamine (2 M inTHF, 1.0 ml) in DMF (5 mL). The crude product was used in the next stepwithout further purification.

1-(3-Amino-4-methylamino-phenyl)-ethanone (66 mg) was prepared byfollowing General Procedure B starting from1-(4-methylamino-3-nitro-phenyl)-ethanone (97 mg) and Pd/C (10% byweight, 10 mg). The crude product was used in the next step withoutfurther purification.

1-[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazol-5-yl]-ethanone(69 mg) was prepared by following General Procedure D starting from1-(3-amino-4-methylamino-phenyl)-ethanone (41 mg),2-amino-6-(trifluoromethoxy)-benzothiazole (59 mg),1,1′-thiocarbonyldiimidazole (44 mg), and EDC (48 mg). LC/MS: m/z 408.

Example 201(5-Methanesulfonyl-1-methyl-1H-benzoimidazol-2-yl)-(6-trifluoromethoxy-benzothiazol-2-yl)-amine

(4-Methanesulfonyl-2-nitro-phenyl)-methyl-amine (182 mg) was prepared byfollowing General Procedure A starting from1-fluoro-4-methanesulfonyl-2-nitro-benzene (219 mg) and methylamine (2 Min THF, 1.0 ml) in DMF (5 mL). The crude product was used in the nextstep without further purification.

4-Methanesulfonyl-N¹-methyl-benzene-1,2-diamine (76 mg) was prepared byfollowing General Procedure B starting from(4-methanesulfonyl-2-nitro-phenyl)-methyl-amine (115 mg) and Pd/C (10%by weight, 10 mg). The crude product was used in the next step withoutfurther purification.

(5-Methanesulfonyl-1-methyl-1H-benzoimidazol-2-yl)-(6-trifluoromethoxy-benzothiazol-2-yl)-amine(72 mg) was prepared by following General Procedure D starting from4-methanesulfonyl-N¹-methyl-benzene-1,2-diamine (50 mg),2-amino-6-(trifluoromethoxy)benzothiazole (59 mg),1,1′-thiocarbonyl-diimidazole (44 mg), and EDC (48 mg). LC/MS: m/z 444.

Example 2022-[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazol-6-yl]-acetamide

2-(3-Methylamino-4-nitro-phenyl)-acetamide (727.0 mg) was prepared byfollowing General Procedure A beginning with2-(3-chloro-4-nitro-phenyl)-acetamide (1.0 g) in methylamine (2.0 M inTHF, 20 mL). The crude product was used in the next step without furtherpurification.

2-(4-Amino-3-methylamino-phenyl)-acetamide (554 mg) was prepared byfollowing General Procedure B beginning with2-(3-methylamino-4-nitro-phenyl)-acetamide (727.0 mg) and Pd/C (20% byweight, 140.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crude product wasused in the next step without further purification.

2-[3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazol-5-yl]-acetamide(240 mg) was prepared by following General Procedure D beginning with2-(4-amino-3-methylamino-phenyl)-acetamide (554 mg),2-amino-6-(trifluoromethoxy)-benzothiazole (600.0 mg),1,1′-thiocarbonyldiimidazole (600.0 mg), and EDC (600.0 mg) in DMF (6.0ml). LCMS: m/z 423.

Examples 203 and 204, as shown in Table 1, are made by proceduresanalogous to those described below for Example 205. Observed m/z valuesfor these examples are as follows. Example 203: 415.8. Example 204:415.8.

Example 2051-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((R)-2-hydroxy-propyl)-amide

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((R)-2-hydroxy-propyl)-amide (30 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (70 mg), (R)-1-amino-propan-2-ol (70 mg), HBTU (200 mg), and DIEA(100 uL) in DMF (1 mL). LC/MS: m/z 449.7. ¹H NMR (DMSO-d₆, 400 MHz): δ8.44-8.41 (t, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.83-7.80 (d, 1H), 7.71(s, 2H), 7.54-7.52 (d, 1H), 3.84-3.80 (m, 1H), 3.70 (s, 3H), 3.25-3.22(m, 2H), 1.10-1.08 (d, 3H), —NH and OH proton signal was not observed.

Examples 206 to 213, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 206: 449.7. Example 207:443.8. Example 208: 477.7. Example 209: 403.7. Example 210: 437.7.Example 211: 446.4. Example 212: 460.0. Example 213: 412.0.

Example 2142-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (3-hydroxy-propyl)-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (3-hydroxy-propyl)-amide (136 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (179 mg), 3-amino-propan-1-ol (40 mg), HBTU (209 mg), and DIEA (200uL) in DMF (1 mL). LC/MS: m/z 415.5.

Examples 215 to 219, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 215: 429.9. Example 216:465.7. Example 217: 495.0. Example 218: 444.9. Example 219: 479.6.

Example 2202-(6-Chloro-1H-benzoimidazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (4-hydroxy-butyl)-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (4-hydroxy-butyl)-amide (37 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (70 mg), 4-amino-butan-1-ol (20 mg), HBTU (80 mg), and DIEA (70 uL)in DMF (1 mL). LC/MS: m/z 429.6.

Example 221, as shown in Table 1, is made by procedures analogous tothose described above for Example 205. An observed m/z value for thisexample is 463.8.

Example 2226-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (4-hydroxy-butyl)-amide

6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (4-hydroxy-butyl)-amide (44 mg) was prepared by General Procedure Fstarting from6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (50 mg), 4-amino-1-butanol (12 mg), HBTU (53 mg), and DIEA (31 uL).LC/MS: m/z 497.1. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.34 (bs, 1H), 8.19 (s,1H), 7.94 (s, 1H), 7.89-7.59 (m, 2H), 7.58-7.40 (m, 1H), 7.36 (d, 1H),4.44 (s, 1H), 3.62 (s, 3H), 3.49-3.39 (m, 2H), 3.32-3.20 (m, 2H),1.67-1.36 (m, 4H).

Example 2231-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((R)-4-hydroxy-3-methyl-butyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((R)-4-hydroxy-3-methyl-butyl)-amide (45 mg) was prepared byfollowing General Procedure F starting1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (80 mg), (R)-4-amino-2-methyl-butan-1-ol (25 mg), HBTU (80 mg), andDIEA (70 uL) in DMF (1 mL). LC/MS: m/z 493.6.

Examples 224 and 225, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 224: 443.9. Example 225:455.8.

Example 2261-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (5-hydroxy-pentyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (5-hydroxy-pentyl)-amide (59 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 5-amino-1-pentanol (21 mg), HBTU (84 mg), and DIEA (48uL). LC/MS m/z 495.0. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.38 (bs, 1H),8.53-8.33 (m, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.83-7.66 (m, 2H), 7.49(d, 1H), 7.36 (d, 1H), 4.38 (s, 1H), 3.64 (s, 3H), 3.41 (q, 2H), 3.27(q, 2H), 1.63-1.41 (m, 4H), 1.41-1.28 (m, 2H).

Examples 227 to 231, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 227: 443.8. Example 228:477.9. Example 229: 523.1. Example 230: 513.5. Example 231: 543.6.

Example 2321-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (trans-4-hydroxy-cyclohexylmethyl)-amide

trans-4-Aminomethyl-cyclohexanol hydrochloride (342 mg) was prepared byfollowing General Procedure L usingtrans-N-Boc-4-aminomethyl-cyclohexanol (500 mg) and hydrogen chloride(5.45 mL, 4.0 M solution in 1,4-dioxane).

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (trans-4-hydroxy-cyclohexylmethyl)-amide (60 mg) was prepared byfollowing General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), trans-4-aminomethyl-cyclohexanol hydrochloride (34 mg),HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 521.0. ¹H NMR (DMSO-d₆, 400MHz): δ 12.40 (bs, 1H), 8.47-8.35 (m, 1H), 8.08 (s, 1H), 7.92 (s, 1H),7.80-7.65 (m, 2H), 7.49 (d, 1H), 7.36 (d, 1H), 4.49 (s, 1H), 3.63 (s,3H), 3.11 (t, 2H), 1.92-1.68 (m, 3H), 1.66-1.18 (m, 4H), 1.17-0.88 (m,3H).

Examples 233 and 234, as shown in Table 1, are made by proceduresanalogous to those described above for Example 232. Observed m/z valuesfor these examples are as follows. Example 233: 469.9. Example 234:503.8.

Example 2352-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide (72 mg) was prepared byfollowing General Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (92 mg), 2-(2-aminoethoxy)-ethanol (30 mg), HBTU (116 mg), and DIEA(67 uL). LC/MS: m/z 446.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.38 (bs, 1H),8.47 (t, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.84-7.58 (m, 2H), 7.48 (d,1H), 7.40 (d, 1H), 4.63 (t, 1H), 3.64 (s, 3H), 3.56 (t, 2H), 3.51 (t,2H), 3.49-3.41 (m, 4H).

Example 2361-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide (87 mg) was prepared byfollowing General Procedure F starting from1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (100 mg), 2-(2-aminoethoxy)-ethanol (30 mg), HBTU (116 mg), andDIEA (67 uL). LC/MS: m/z 480.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.48 (bs,1H), 8.48 (t, 1H), 8.27 (s, 1H), 8.11 (s, 1H), 7.78 (d, 1H), 7.69 (d,1H), 7.51 (d, 1H), 7.36 (d, 1H), 3.68 (s, 3H), 3.57 (t, 2H), 3.52 (t,2H), 3.49-3.41 (m, 4H), —OH proton signal was not observed.

Examples 237 and 238, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 237: 514.7. Example 238:496.7.

Example 239, as shown in Table 1, is made by procedures analogous tothose described below for Example 240. An observed m/z value for thisexample is 538.8.

Example 2402-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methylamino-ethyl)-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide hydrochloride

(2-{2-(6-Chloro-benzothiazol-2-ylamino)-5-[2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-benzoimidazol-1-yl}-ethyl)-methyl-carbamicacid tert-butyl ester (73 mg) was prepared by following GeneralProcedure F starting from1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (145 mg), 2-(2-amino-ethoxy)-ethanol (35 mg), HBTU (125 mg), andDIEA (100 uL) in DMF (1 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methylamino-ethyl)-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide dihydrochloride (60 mg) wasprepared by following General Procedure L starting from(2-{2-(6-chloro-benzothiazol-2-ylamino)-5-[2-(2-hydroxy-ethoxy)-ethylcarbamoyl]-benzoimidazol-1-yl}-ethyl)-methyl-carbamicacid tert-butyl ester (73 mg) in 4M HCl in dioxane (1 mL). LC/MS: m/z488.5.

Examples 241 to 243, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 241: 539.4. Example 242:510.0. Example 243: 459.9.

Example 244, as shown in Table 1, is made by procedures analogous tothose described below for Example 245. An observed m/z value for thisexample is 510.7.

Example 2451-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-2-methyl-propoxy)-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-2-methyl-propoxy)-ethyl]-amide (5 mg) was prepared byfollowing General Procedure X starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethyl)-amide (100 mg), 1,2-epoxy-2-methyl-propane (19mg), and KOH (19 mg) in DMF. LC/MS: m/z 524.7.

Example 2461-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(3-hydroxy-propoxy)-ethyl]-amide

Toluene-4-sulfonic acid 3-benzyloxy-propyl ester (14.4 g) was preparedby following General Procedure V starting from 3-benzyloxy-1-propanol(8.4 g), p-toluenesulfonyl chloride (12.52 g), and DMAP (84 mg).

Dibenzyl-[2-(3-benzyloxy-propoxy)-ethyl]-amine (860 mg) was prepared byfollowing General Procedure W starting from toluene-4-sulfonic acid3-benzyloxy-propyl ester (1.33 g), N,N-dibenzyl-2-aminoethanol (1.0 g),50% aqueous sodium hydroxide solution (1.66 g in 1.66 mL of water), andtetrabutylammonium hydrogen sulfate (141 mg).

3-(2-Amino-ethoxy)-propan-1-ol (229 mg) was prepared by followingGeneral Procedure B starting fromdibenzyl-[2-(3-benzyloxy-propoxy)-ethyl]-amine (860 mg) and Pd/C (86mg).

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(3-hydroxy-propoxy)-ethyl]-amide (85 mg) was prepared byfollowing General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (82 mg), 3-(2-amino-ethoxy)-propan-1-ol (48 mg), HBTU (91 mg), andDIEA (52 uL). LC/MS: m/z 510.0.

Example 247, as shown in Table 1, is made by procedures analogous tothose described below for Example 249. An observed m/z value for thisexample is 513.1.

Example 248, as shown in Table 1, is made by procedures analogous tothose described above for Example 246. An observed m/z value for thisexample is 459.9.

Example 2492-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(3-fluoro-propoxy)-ethyl]-amide

Dibenzyl-[2-(3-fluoro-propoxy)-ethyl]-amine (770 mg) was prepared byfollowing General Procedure S starting fromdibenzyl-(2-chloro-ethyl)-amine (1 g), 3-fluoro-propan-1-ol (295 mg),50% (w/w) KOH solution (4.25 mL) and tetrabutylammonium bromide (130 mg)in dioxane (4.25 mL).

2-(3-Fluoro-propoxy)-ethylamine (94 mg) was prepared by followingGeneral Procedure T starting fromdibenzyl-[2-(3-fluoro-propoxy)-ethyl]-amine (450 mg) and Pd—C (90 mg) inmethanol (1.5 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(3-fluoro-propoxy)-ethyl]-amide (12 mg) was prepared byfollowing General Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (55 mg), 2-(3-fluoro-propoxy)-ethylamine (50 mg), HBTU (60 mg), andDIEA (50 uL) in DMF (800 uL). LC/MS: m/z 463.0.

Example 2501-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [3-(2-hydroxy-ethoxy)-propyl]-amide

Toluene-4-sulfonic acid 2-benzyloxy-ethyl ester (11.3 g) was prepared byfollowing General Procedure V starting from 2-benzyloxyethanol (9.57 g),p-toluenesulfonyl chloride (16.73 g), and DMAP (96 mg).

Dibenzyl-[3-(2-benzyloxy-ethoxy)-propyl]-amine (378 mg) was prepared byfollowing General Procedure W starting from toluene-4-sulfonic acid2-benzyloxy-ethyl ester (1.0 g), 3-dibenzylamino-propan-1-ol (1.08 g),50% aqueous sodium hydroxide solution (1.3 g in 1.3 mL of water), andtetrabutylammonium hydrogen sulfate (111 mg).

2-(3-Amino-propoxy)-ethanol (49 mg) was prepared by following GeneralProcedure B starting from dibenzyl-[3-(2-benzyloxy-ethoxy)-propyl]-amine(378 mg) and Pd/C (38 mg).

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [3-(2-hydroxy-ethoxy)-propyl]-amide (41 mg) was prepared byfollowing General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (82 mg), 2-(3-amino-propoxy)-ethanol (49 mg), HBTU (91 mg), andDIEA (52 uL). LC/MS: m/z 509.8.

Examples 251 to 256, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 251: 528.9. Example 252:529.0. Example 253: 535.0. Example 254: 535.1. Example 255: 485.0.Example 256: 539.5.

Example 257, as shown in Table 1, is made by procedures analogous tothose described above for Example 47. An observed m/z value for thisexample is 481.8.

Examples 258 and 259, as shown in Table 1, are made by proceduresanalogous to those described above for Example 249. Observed m/z valuesfor these examples are as follows. Example 258: 516.8. Example 259:465.8.

Example 2601-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-methoxy-ethoxy)-ethyl]-amide

1-Azido-2-(2-methoxy-ethoxy)-ethane (607 mg) was prepared by followingGeneral Procedure U starting from 1-bromo-2-(2-methoxy-ethoxy)-ethane(1.0 g) and sodium azide (1.07 g). The crude product was used in thenext step without further purification.

2-(2-Methoxy-ethoxy)-ethylamine (425 mg) was prepared by followingGeneral Procedure B starting from 1-azido-2-(2-methoxy-ethoxy)-ethane(607 mg) and 10% Pd/C (60 mg). The crude product was used in the nextstep without further purification.

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-methoxy-ethoxy)-ethyl]-amide (44 mg) was prepared byfollowing General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (75 mg), 2-(2-methoxy-ethoxy)-ethylamine (24 mg), HBTU (84 mg), andDIEA (48 uL). LC/MS: m/z 511.0. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.40 (bs,1H), 8.50 (t, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.74 (d,1H), 7.50 (d, 1H), 7.36 (d, 1H), 3.64 (s, 3H), 3.59-3.53 (m, 4H),3.49-3.41 (m, 4H), 3.25 (s, 3H).

Examples 261 and 262, as shown in Table 1, are made by proceduresanalogous to those described above for Example 260. Observed m/z valuesfor these examples are as follows. Example 261: 461.0. Example 262:493.7.

Examples 263 and 264, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 263: 520.8. Example 264:520.8.

Example 2651-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-cyano-ethoxy)-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-cyano-ethoxy)-ethyl]-amide (54 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (82 mg), 3-(2-amino-ethoxy)-propionitrile hydrochloride (60 mg),HBTU (91 mg), and DIEA (52 uL). LC/MS: m/z 506.0.

Example 2662-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-cyano-ethoxy)-ethyl]-amide

[2-(2-Cyano-ethoxy)-ethyl]-carbamic acid tert-butyl ester (430 mg) wasprepared starting from (2-hydroxy-ethyl)-carbamic acid tert-butyl ester(320 mg) in acrylonitrile (1.5 mL). The reaction was heated to 50° C.for 1 h. The reaction was added to ethyl acetate (20 mL) and water (20mL). The phases were separated and the aqueous phase was extracted twicewith ethyl acetate. The combined organics were dried over sodium sulfateand then filtered. The solvent was evaporated and crude compound waspurified by flash chromatography using hexane:ethyl acetate gradient.

3-(2-Amino-ethoxy)-propionitrile hydrochloride (300 mg) was prepared byfollowing General Procedure L starting from[2-(2-cyano-ethoxy)-ethyl]-carbamic acid tert-butyl ester (430 mg) in 2MHCl in ether (2 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-cyano-ethoxy)-ethyl]-amide (60 mg) was prepared by followingGeneral Procedure F starting2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (70 mg), 3-(2-amino-ethoxy)-propionitrile hydrochloride (100 mg),HBTU (85 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 456.0.

Example 2671-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-carbamoylmethoxy-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-carbamoylmethoxy-ethyl)-amide (20 mg) was prepared on solidphase starting from[2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethoxy]-acetic acid (204 mg),HBTU (230 mg), DIEA (100 uL) and Rink amide resin (320 mg) in DMF (20mL). The reaction was stirred at room temperature for 1 h and thenwashed with DMF (3×20 mL each).

The reaction was then stirred at room temperature with 20% (v/v)piperidine in DMF (10 mL) for 1 h. The reaction was washed with DMF(3×20 mL each). In the next step the reaction was stirred at roomtemperature with1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (244 mg), HBTU (230 mg) and DIEA (100 uL) in DMF (10 mL) for 2 hand washed with DMF (3×20 mL each). In the last step the reaction wasstirred with TFA (10 mL) for 30 min and then filtered. The filtrate wasevaporated and crude compound was purified by flash chromatography usingDCM: 10% methanol in DCM gradient. LC/MS: m/z 508.6.

Example 2681-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-amino-ethoxy)-ethyl]-amide

[2-(2-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethoxy)-ethyl]-carbamicacid 9H-fluoren-9-ylmethyl ester (106 mg) was prepared by followingGeneral Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (80 mg), [2-(2-amino-ethoxy)-ethyl]-carbamic acid9H-fluoren-9-ylmethyl ester (80 mg), HBTU (95 mg), and DIEA (70 uL) inDMF (1 mL).

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-amino-ethoxy)-ethyl]-amide (70 mg) was prepared by followingGeneral Procedure O starting from[2-(2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethoxy)-ethyl]-carbamicacid 9H-fluoren-9-ylmethyl ester (106 mg), 20% (v/v) piperidine in DMF(1.5 mL). LC/MS: m/z 494.5.

Examples 269 and 270, as shown in Table 1, are made by proceduresanalogous to those described above for Example 268. Observed m/z valuesfor these examples are as follows. Example 269: 444.7. Example 270:445.7.

Example 2711-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-methylamino-ethoxy)-ethyl]-amide hydrochloride

[2-(2-Dibenzylamino-ethoxy)-ethyl]-methyl-carbamic acid tert-butyl ester(200 mg) was prepared by following General Procedure S starting fromdibenzyl-(2-chloro-ethyl)-amine (400 mg),(2-hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (525 mg), 50%(w/w) KOH solution (1.8 mL) and tetrabutylammonium bromide (57.7 mg) indioxane (1.8 mL).

[2-(2-Amino-ethoxy)-ethyl]-methyl-carbamic acid tert-butyl ester (100mg) was prepared following General Procedure T starting from[2-(2-dibenzylamino-ethoxy)-ethyl]-methyl-carbamic acid tert-butyl ester(200 mg) and Pd—C (40 mg) in methanol (1.5 mL).

Methyl-[2-(2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethoxy)-ethyl]-carbamicacid tert-butyl ester (69 mg) was prepared by following GeneralProcedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (82 mg), [2-(2-amino-ethoxy)-ethyl]-methyl-carbamic acid tert-butylester (87 mg), HBTU (91 mg), and DIEA (52 uL).

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-methylamino-ethoxy)-ethyl]-amide dihydrochloride (53 mg) wasprepared by following General Procedure L usingmethyl-[2-(2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-ethoxy)-ethyl]-carbamicacid tert-butyl ester (60 mg) and hydrogen chloride (250 uL, 4.0 Msolution in 1,4-dioxane). LC/MS: m/z 509.0.

Example 272, as shown in Table 1, is made by procedures analogous tothose described above for Example 271. An observed m/z value for thisexample is 458.9.

Example 2731-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-dimethylamino-ethoxy)-ethyl]-amide

[2-(2-Dibenzylamino-ethoxy)-ethyl]-dimethyl-amine was prepared followingGeneral Procedure S starting from dibenzyl-(2-chloro-ethyl)-amine (640mg), 2-dimethylamino-ethanol (325 mg), 50% (w/w) KOH solution (3 mL) andtetrabutylammonium bromide (95 mg) in dioxane (3 mL).

[2-(2-Amino-ethoxy)-ethyl]-dimethyl-amine (100 mg) was preparedfollowing General Procedure T starting from[2-(2-dibenzylamino-ethoxy)-ethyl]-dimethyl-amine (430 mg) and Pd—C (86mg) in methanol (1 mL).

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-dimethylamino-ethoxy)-ethyl]-amide (25 mg) was prepared byfollowing General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (93 mg), [2-(2-amino-ethoxy)-ethyl]-dimethyl-amine (60 mg), HBTU(103 mg), and DIEA (59 uL). LC/MS: m/z 523.0.

Example 274, as shown in Table 1, is made by procedures analogous tothose described above for Example 273. An observed m/z value for thisexample is 473.0.

Example 2751-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-acetylamino-ethoxy)-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-acetylamino-ethoxy)-ethyl]-amide (25 mg) was prepared byfollowing General Procedure R starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-amino-ethoxy)-ethyl]-amide (50 mg), acetyl chloride (1-2drops) and triethylamine (30 uL) in DCM (1 mL). LC/MS: m/z 536.5.

Example 2761-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-methanesulfonylamino-ethoxy)-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-methanesulfonylamino-ethoxy)-ethyl]-amide (22 mg) wasprepared by following General Procedure Q starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-amino-ethoxy)-ethyl]-amide (50 mg), methanesulfonyl chloride(1-2 drops) and triethylamine (30 uL) in DCM (1 mL). LC/MS: m/z 572.4.

Example 277, as shown in Table 1, is made by procedures analogous tothose described below for Example 278. An observed m/z value for thisexample is 477.7.

Example 2782-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethanesulfonyl)-ethyl]-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethylsulfanyl)-ethyl]-amide (70 mg) was prepared byfollowing General Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (70 mg), 2-(2-amino-ethylsulfanyl)-ethanol (50 mg), HBTU (150 mg),and DIEA (100 uL) in DMF (1 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethanesulfonyl)-ethyl]-amide (40 mg) was prepared byfollowing General Procedure M starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethylsulfanyl)-ethyl]-amide (60 mg) and 32 wt %peracetic acid solution (100 uL) in DCM (1 mL). LC/MS: m/z 493.8.

Example 2792-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-fluoro-ethylamino)-ethyl]-amide hydrochloride

N,N-Dibenzyl-N′-(2-fluoro-ethyl)-ethane-1,2-diamine (160 mg) wasprepared by following General Procedure S starting fromdibenzyl-(2-chloro-ethyl)-amine (520 mg), 2-fluoro-ethylaminehydrochloride (250 mg), DIEA (900 uL) and tetrabutylammonium bromide (60mg) in DMF (2 mL).

(2-Dibenzylamino-ethyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester(216 mg) was prepared starting fromN,N-dibenzyl-N′-(2-fluoro-ethyl)-ethane-1,2-diamine (160 mg), Boc₂O (146mg) and triethylamine (170 uL) in DCM (1 mL). The reaction was stirredat room temperature for 1 h. The reaction was added to DCM and saturatedsodium bicarbonate solution. The phases were separated, the combinedorganics were dried over sodium sulfate and then filtered. The filtratewas evaporated and compound was isolated without further purification.

(2-Amino-ethyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester (95 mg)was prepared by following General Procedure T starting from(2-dibenzylamino-ethyl)-(2-fluoro-ethyl)-carbamic acid tert-butyl ester(216 mg) and Pd—C (40 mg) in methanol (1 mL).

(2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-(2-fluoro-ethyl)-carbamicacid tert-butyl ester (70 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (70 mg), (2-amino-ethyl)-(2-fluoro-ethyl)-carbamic acid tert-butylester (90 mg), HBTU (100 mg), and DIEA (70 uL) in DMF (1.5 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-fluoro-ethylamino)-ethyl]-amide dihydrochloride (65 mg) wasprepared by following General Procedure L starting from(2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}uoro-ethyl)-carbamicacid tert-butyl ester (70 mg) in 4M HCl in dioxane (1 mL). LC/MS: m/z446.6.

Examples 280 to 284, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 280: 482.9. Example 281:481.5. Example 282: 539.0. Example 283: 570.8. Example 284: 496.9.

Example 285, as shown in Table 1, is made by procedures analogous tothose described below for Example 286. An observed m/z value for thisexample is 479.6.

Example 2863-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide

3-Methylamino-4-nitro-benzoic acid ethyl ester (2.8 g) was prepared byfollowing General Procedure A starting from 3-fluoro-4-nitro-benzoicacid ethyl ester (3 g) and 2 M methylamine in THF (15 mL) in DMF (15mL).

4-Amino-3-methylamino-benzoic acid ethyl ester (2.1 g) was prepared byfollowing General Procedure B starting from3-methylamino-4-nitro-benzoic acid ethyl ester (2.8 g) and Pd—C (560 mg)in methanol (25 mL).

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylicacid ethyl ester (2.8 g) was prepared by following General Procedure Dstarting from 6-trifluoromethoxy-benzothiazol-2-ylamine (2.9 g),4-amino-3-methylamino-benzoic acid ethyl ester (2.1 g), thioCDI (2.2 g)and EDC (2.4 g) in DMF (30 mL).

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylicacid (2.5 g) was prepared by following General Procedure E starting from3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylicacid ethyl ester (2.8 g) and 2 N NaOH (6 mL) in methanol:THF (1:1, 12mL).

3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide (50 mg) was prepared byfollowing General Procedure F starting from3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylicacid (80 mg), 2-(2-amino-ethoxy)-ethanol (24 mg), HBTU (80 mg), and DIEA(70 uL) in DMF (1 mL). LC/MS: m/z 495.5.

Example 287, as shown in Table 1, is made by procedures analogous tothose described below for Example 288. An observed m/z value for thisexample is 429.6.

Example 2882-(6-Chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide

2-(6-Chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylicacid ethyl ester (1.2 g) was prepared by following General Procedure Dstarting from 6-chloro-benzothiazol-2-ylamine (1.2 g),4-amino-3-methylamino-benzoic acid ethyl ester (1.2 g), thioCDI (1 g)and EDC (1.1 g) in DMF (20 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylicacid (1 g) was prepared by following General Procedure E starting from2-(6-chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylicacid ethyl ester (1.2 g) and 2 N NaOH (5 mL) in methanol:THF (1:1, 20mL).

2-(6-Chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide (40 mg) was prepared byfollowing General Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-3-methyl-3H-benzoimidazole-5-carboxylicacid (70 mg), 2-(2-amino-ethoxy)-ethanol (23 mg), HBTU (80 mg), and DIEA(70 uL) in DMF (1 mL). LC/MS: m/z 445.6.

Examples 289 to 291, as shown in Table 1, are made by proceduresanalogous to those described above for Example 55. Observed m/z valuesfor these examples are as follows. Example 289: 476.6. Example 290:426.6. Example 291: 426.5.

Example 2922-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [(R)-1-(2-hydroxy-ethyl)-pyrrolidin-3-yl]-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [(R)-1-(2-hydroxy-ethyl)-pyrrolidin-3-yl]-amide (25 mg) wasprepared starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (R)-pyrrolidin-3-ylamide dihydrochloride (200 mg), 2-bromo-ethanol(50 uL) and Cs₂CO₃ (300 mg) in DMF (1 mL). The reaction was heated to50° C. for 8 h. The reaction was filtered and purified with silica gelchromatography using DCM: 10% methanol in DCM (100:0 to 0:100) as aneluent system to give pure product. LC/MS: m/z 470.6.

Example 2932-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [(S)-1-(2-hydroxy-ethyl)-pyrrolidin-3-yl]-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [(S)-1-(2-hydroxy-ethyl)-pyrrolidin-3-yl]-amide (20 mg) wasprepared starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (S)-pyrrolidin-3-ylamide dihydrochloride (200 mg), 2-bromo-ethanol(50 uL) and Cs₂CO₃ (300 mg) in DMF (1 mL). The reaction was heated to50° C. for 8 h. The reaction was filtered and purified with silica gelchromatography using DCM 10% methanol in DCM (100:0 to 0:100) as aneluent system to give pure product. LC/MS: m/z 470.8.

Example 2941-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [1-((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]-amide

3-{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg)was prepared by following General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (408 mg), 3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester(220 mg), HBTU (457 mg), and DIEA (350 uL) in DMF (3 mL).

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid pyrrolidin-3-ylamide dihydrochloride (330 mg) was prepared byfollowing General Procedure L starting from3-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg)in 4M HCl in dioxane (2 mL).

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [1-((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]-amide (15 mg) wasprepared using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid pyrrolidin-3-ylamide dihydrochloride (47 mg), (R)-2-methyl-oxirane(excess) and DIEA (35 uL) in DMF (1 mL). The reaction was stirred at 80°C. overnight. The pure product was isolated through silica gelchromatography using DCM: (10%) methanol in DCM (from 100:0 to 0:100) aseluent system. LC/MS: m/z 534.6.

Example 2952-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [(R)-1-((R)-2-hydroxy-propionyl)-pyrrolidin-3-yl]-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [(R)-1-((R)-2-hydroxy-propionyl)-pyrrolidin-3-yl]-amide (20 mg) wasprepared by following General Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (50 mg), (R)-1-((R)-3-amino-pyrrolidin-1-yl)-2-hydroxy-propan-1-one(100 mg), HBTU (150 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z498.6.

Example 2962-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [(R)-1-((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]-amide

[(R)-1-((R)-2-Hydroxy-propionyl)-pyrrolidin-3-yl]-carbamic acidtert-butyl ester (500 mg) was prepared by following General Procedure Fstarting from (R)-2-hydroxy-propionic acid (200 mg),(R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (372 mg), HBTU (800mg), and DIEA (400 uL) in DMF (4 mL).

[(R)-1-((R)-2-Hydroxy-propyl)-pyrrolidin-3-yl]-carbamic acid tert-butylester (244 mg) was prepared from[(R)-1-((R)-2-hydroxy-propionyl)-pyrrolidin-3-yl]-carbamic acidtert-butyl ester (500 mg) and 1 M borane in THF (6 mL). The reaction wasstirred at room temperature for 30 min and then stirred at 50° C. for 8h. The reaction was added to methanol (20 mL). The solvent wasevaporated and crude compound was purified by flash chromatography usingDCM:methanol gradient.

(R)-1-((R)-3-Amino-pyrrolidin-1-yl)-propan-2-ol dihydrochloride (140 mg)was prepared by following General Procedure L starting from[(R)-1-((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]-carbamic acid tert-butylester (244 mg) and DCM (2 mL) in 4M HCl in dioxane (2 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [(R)-1-((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]-amide (20 mg) wasprepared by following General Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (60 mg), (R)-1-((R)-3-amino-pyrrolidin-1-yl)-propan-2-ol (100 mg),HBTU (180 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 484.7. ¹H NMR(DMSO-d₆, 400 MHz): δ 8.43 (m, 1H), 8.08 (s, 1H), 7.93-7.92 (d, 1H),7.75 (br.m, 1H), 7.47-7.45 (br.d, 1H), 7.40-7.37 (m, 1H), 4.52-4.42 (m,2H), 3.77-3.73 (m, 1H), 3.66 (s, 3H), 2.92-2.78 (m, 2H), 2.63-2.60 (m,2H), 2.46-2.43 (m, 2H), 2.19-2.14 (m, 1H), 1.86-1.78 (m, 1H) 1.07-1.06(d, 3H) —NH and OH proton signal was not observed.

Example 297, as shown in Table 1, is made by procedures analogous tothose described above for Example 296. An observed m/z value for thisexample is 518.7.

Example 2981-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [1-(2-hydroxy-2-methyl-propyl)-pyrrolidin-3-yl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [1-(2-hydroxy-2-methyl-propyl)-pyrrolidin-3-yl]-amide (16 mg) wasprepared using1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid pyrrolidin-3-ylamide dihydrochloride (47 mg), 2,2-dimethyl-oxirane(excess) and DIEA (70 uL) in DMF (1 mL). The reaction was stirred at 80°C. overnight. The pure product was isolated through silica gelchromatography using DCM: (10%) methanol in DCM (from 100:0 to 0:100) aseluent system. LC/MS: m/z 548.7.

Example 299, as shown in Table 1, is made by procedures analogous tothose described above for Example 266. An observed m/z value for thisexample is 498.5.

Example 3002-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [1-(2-methanesulfonylamino-ethyl)-pyrrolidin-3-yl]-amide

[2-(3-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-pyrrolidin-1-yl)-ethyl]-carbamicacid tert-butyl ester (56 mg) was prepared by following GeneralProcedure P starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid pyrrolidin-3-ylamide dihydrochloride (84 mg),(2-oxo-ethyl)-carbamic acid tert-butyl ester (40 mg), and Na(OAc)₃BH (65mg) in DCM (2 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [1-(2-amino-ethyl)-pyrrolidin-3-yl]-amide trihydrochloride (46 mg)was prepared by following General Procedure L starting from[2-(3-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-pyrrolidin-1-yl)-ethyl]-carbamicacid tert-butyl ester (56 mg) in 4M HCl in dioxane (1 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [1-(2-methanesulfonylamino-ethyl)-pyrrolidin-3-yl]-amide (15 mg)was prepared by following General Procedure Q starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [1-(2-amino-ethyl)-pyrrolidin-3-yl]-amide dihydrochloride(46 mg),methanesulfonyl chloride (1-2 drops) and triethylamine (30 uL) in DCM (1mL). LC/MS: m/z 547.6.

Example 3012-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid [1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide

4-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (160 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid (180 mg), 4-amino-piperidine-1-carboxylic acid tert-butyl ester(150 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid piperidin-4-ylamide dihydrochloride (150 mg) was prepared byfollowing General Procedure L starting from4-{[2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (160 mg) in 4M HCl in dioxane (2 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid [1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide (52 mg) was prepared byfollowing General Procedure P starting from2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid piperidin-4-ylamide dihydrochloride (145 mg), [1,4]dioxane-2,5-diol(55 mg), and Na(OAc)₃BH (95 mg) in DCM (2 mL). LC/MS: m/z 528.6.

Example 302, as shown in Table 1, is made by procedures analogous tothose described above for Example 55. An observed m/z value for thisexample is 454.5.

Example 3032-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [1-(2-hydroxy-ethyl)-piperidin-4-ylmethyl]-amide

4-({[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (155 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (150 mg), 4-aminomethyl-piperidine-1-carboxylic acid tert-butylester (100 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (piperidin-4-ylmethyl)-amide dihydrochloride (150 mg) was preparedby following General Procedure L starting from4-({[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (155 mg) in 4M HCl in dioxane (2 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [1-(2-hydroxy-ethyl)-piperidin-4-ylmethyl]-amide (35 mg) wasprepared by following General Procedure P starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (piperidin-4-ylmethyl)-amide dihydrochloride (135 mg),[1,4]dioxane-2,5-dio (65 mg), and Na(OAc)₃BH (95 mg) in DCM (2 mL).LC/MS: m/z 498.5.

Example 3042-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid [1-(2-hydroxy-ethyl)-piperidin-4-ylmethyl]-amide

4-({[2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (160 mg) was prepared by following GeneralProcedure F starting from2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid (180 mg), 4-aminomethyl-piperidine-1-carboxylic acid tert-butylester (150 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid (piperidin-4-ylmethyl)-amide dihydrochloride (145 mg) was preparedby following General Procedure L starting from4-({[2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester (160 mg) in 4M HCl in dioxane (2 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid [1-(2-hydroxy-ethyl)-piperidin-4-ylmethyl]-amide (45 mg) wasprepared by following General Procedure P starting from2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid (piperidin-4-ylmethyl)-amide dihydrochloride (136 mg),[1,4]dioxane-2,5-diol (54 mg), and Na(OAc)₃BH (95 mg) in DCM (2 mL).LC/MS: m/z 542.7.

Example 305, as shown in Table 1, is made by procedures analogous tothose described below for Example 306. An observed m/z value for thisexample is 520.6.

Example 306[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazol-5-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone

[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazol-5-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone(315 mg) was prepared by following General Procedure F starting2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (358 mg), 2-piperazin-1-yl-ethanol (143 mg), HBTU (419 mg), andDIEA (350 uL) in DMF (3 mL). LC/MS: m/z 470.6.

Example 307, as shown in Table 1, is made by procedures analogous tothose described above for Example 205. An observed m/z value for thisexample is 533.5.

Example 308, as shown in Table 1, is made by procedures analogous tothose described below for Example 313. An observed m/z value for thisexample is 511.5.

Examples 309 and 310, as shown in Table 1, are made by proceduresanalogous to those described above for Example 55. Observed m/z valuesfor these examples are as follows. Example 309: 441.6. Example 310:441.8.

Examples 311 and 312, as shown in Table 1, are made by proceduresanalogous to those described below for Example 313. Observed m/z valuesfor these examples are as follows. Example 311: 526.9. Example 312:526.7.

Example 3132-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [1-(2-dimethylamino-acetyl)-piperidin-4-yl]-amide

4-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (800 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (716 mg), 4-amino-piperidine-1-carboxylic acid tert-butyl ester(500 mg), HBTU (952 mg), and DIEA (700 uL) in DMF (5 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid piperidin-4-ylamide dihydrochloride (750 mg) was prepared byfollowing General Procedure L starting from4-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (800 mg) in 4M HCl in dioxane (5 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [1-(2-dimethylamino-acetyl)-piperidin-4-yl]-amide (52 mg) wasprepared by following General Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid piperidin-4-ylamide dihydrochloride (88 mg), dimethylamino-aceticacid (26 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z525.5. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.40-8.38 (d, 1H), 8.11 (s, 1H),7.96 (m, 1H), 7.80-7.78 (d, 1H), 7.55-7.50 (m, 2H), 7.43-7.40 (d, 1H),4.43-4.25 (m, 2H), 4.09-4.08 (br.m, 1H), 3.68 (s, 3H), 3.67-3.65 (m,1H), 3.57-3.50 (m, 1H), 3.22-3.17 (m, 1H), 2.93-2.82 (m, 6H), 1.96-1.89(m, 2H), 1.59-1.46 (m, 2H), 1.30-1.25 (m, 1H) —NH proton signal was notobserved.

Examples 314 and 315, as shown in Table 1, are made by proceduresanalogous to those described above for Example 313. Observed m/z valuesfor these examples are as follows. Example 314: 539.7. Example 315:583.7.

Example 3162-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid ((R)-1-methyl-pyrrolidin-3-yl)-amide

(R)-3-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester (55 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (70 mg), (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester(45 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (R)-pyrrolidin-3-ylamide dihydrochloride (45 mg) was prepared byfollowing General Procedure L starting from(R)-3-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester (55 mg) in 4M HCl in dioxane (1 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid ((R)-1-methyl-pyrrolidin-3-yl)-amide (42 mg) was prepared byfollowing General Procedure P starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (R)-pyrrolidin-3-ylamide dihydrochloride (51 mg), 37% formaldehyde(500 uL), and Na(OAc)₃BH (40 mg) in DCM (500 uL). LC/MS: m/z 440.5.

Example 3172-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid ((S)-1-methyl-pyrrolidin-3-yl)-amide

(S)-3-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester (65 mg) was prepared by following GeneralProcedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (70 mg), (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester(46 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (S)-pyrrolidin-3-ylamide dihydrochloride (51 mg) was prepared byfollowing General Procedure L starting from(S)-3-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-pyrrolidine-1-carboxylicacid tert-butyl ester (65 mg) in 4M HCl in dioxane (1 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid ((S)-1-methyl-pyrrolidin-3-yl)-amide (35 mg) was prepared byfollowing General Procedure P starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (S)-pyrrolidin-3-ylamide dihydrochloride (45 mg), 37% formaldehyde(500 uL), and Na(OAc)₃BH (32 mg) in DCM (500 uL). LC/MS: m/z 440.7.

Examples 318 to 321, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 318: 469.8. Example 319:455.8. Example 320: 519.6. Example 321: 442.8.

Example 3221-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methanesulfonylamino-ethyl)-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methanesulfonylamino-ethyl)-amide (57 mg) was prepared byfollowing General Procedure Q starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-amino-ethyl)-amide dihydrochloride (75 mg), methanesulfonylchloride (16 mg), and triethylamine (62 uL). LC/MS: m/z 529.6.

Example 3231-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-dimethylamino-acetylamino)-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-dimethylamino-acetylamino)-ethyl]-amide (62 mg) was preparedby following General Procedure F starting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-amino-ethyl)-amide dihydrochloride (60 mg), N,N-dimethylglycinehydrochloride (18 mg), HBTU (57 mg), and DIEA (33 uL). LC/MS: m/z 536.8.¹H NMR (DMSO-d₆, 400 MHz): δ 12.37 (bs, 1H), 8.48 (s, 1H), 8.08 (s, 1H),8.04 (s, 1H), 7.94 (s, 1H), 7.80-7.65 (m, 2H), 7.49 (d, 1H), 7.37 (d,1H), 3.76-3.46 (m, 5H), 2.97 (s, 2H), 2.89 (s, 2H), 2.25 (s, 6H).

Example 3242-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-dimethylamino-acetylamino)-ethyl]-amide

(2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-carbamicacid tert-butyl ester (290 mg) was prepared by following GeneralProcedure F using2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (300 mg), (2-amino-ethyl)-carbamic acid tert-butyl ester (147 mg),HBTU (380 mg), and DIEA (219 uL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-amino-ethyl)-amide dihydrochloride (225 mg) was prepared byfollowing General Procedure L using(2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-ethyl)-carbamicacid tert-butyl ester (250 mg) and hydrogen chloride (1.25 mL, 4.0 Msolution in 1,4-dioxane).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-dimethylamino-acetylamino)-ethyl]-amide (64 mg) was preparedby following General Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-amino-ethyl)-amide dihydrochloride (75 mg), N,N-dimethylglycinehydrochloride (24 mg), HBTU (79 mg), and DIEA (46 uL). LC/MS: m/z 486.9.¹H NMR (DMSO-d₆, 400 MHz): δ 12.38 (bs, 1H), 8.64-8.44 (m, 1H), 8.22(bs, 1H), 8.08 (s, 1H), 7.93 (s, 1H), 7.83-7.59 (m, 2H), 7.55-7.45 (m,1H), 7.41 (d, 1H), 3.79-3.56 (m, 5H), 3.44-3.34 (m, 2H), 3.20-3.09 (m,2H), 2.71 (s, 6H).

Examples 325 and 326, as shown in Table 1, are made by proceduresanalogous to those described above for Example 313. Observed m/z valuesfor these examples are as follows. Example 325: 508.0. Example 326:524.0.

Examples 327 to 334, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 327: 502.9. Example 328:501.5. Example 329: 518.5. Example 330: 519.6. Example 331: 483.7.Example 332: 527.7. Example 333: 519.0. Example 334: 468.9.

Example 3352-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(4,4-difluoro-piperidin-1-yl)-ethyl]-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2,2-dimethoxy-ethyl)-amide (700 mg) was prepared by followingGeneral Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (716 mg), 2,2-dimethoxy-ethylamine (265 mg), HBTU (952 mg), andDIEA (700 uL) in DMF (5 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-oxo-ethyl)-amide (574 mg) was prepared starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2,2-dimethoxy-ethyl)-amide (700 mg) in 4M HCl-dioxane (3 mL). Thereaction was heated to 50° C. for 5 h. The solvent was evaporated togive crude product.

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2 (4,4-difluoro-piperidin-1-yl)-ethyl]-amide (45 mg) was preparedby following General Procedure P starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-oxo-ethyl)-amide (80 mg), 4,4-difluoro-piperidine (36 mg), andNa(OAc)₃BH (65 mg) in DCM (2 mL). LC/MS: m/z 504.5. ¹H NMR (DMSO-d₆, 400MHz): δ 8.97-8.88 (m, 1H), 8.14-8.12 (m, 1H), 7.97-7.96 (m, 1H),7.88-7.80 (m, 1H), 7.56-7.52 (m, 2H), 7.43-7.40 (m, 1H), 4.08-4.05 (m,1H), 3.74-3.69 (m, 7H), 3.57-3.47 (m, 1H), 3.46-3.17 (m, 3H), 2.46-2.43(m, 3H), —NH proton signal was not observed.

Example 336, as shown in Table 1, is made by procedures analogous tothose described above for Example 335. An observed m/z value for thisexample is 504.7.

Examples 337 and 338, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 337: 534.0. Example 338:483.8.

Example 339, as shown in Table 1, is made by procedures analogous tothose described above for Example 55. An observed m/z value for thisexample is 469.9.

Examples 340 to 342, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 340: 470.8. Example 341:504.7. Example 342: 568.8.

Examples 343 to 347, as shown in Table 1, are made by proceduresanalogous to those described above for Example 104. Observed m/z valuesfor these examples are as follows. Example 343: 401.8. Example 344:464.9. Example 345: 414.8. Example 346: 478.9. Example 347: 428.8.

Examples 348 to 362, as shown in Table 1, are made by proceduresanalogous to those described above for Example 205. Observed m/z valuesfor these examples are as follows. Example 348: 492.4. Example 349:442.6. Example 350: 476.6. Example 351: 520.5. Example 352: 470.5.Example 353: 504.5. Example 354: 468.5. Example 355: 547.5. Example 356:497.5. Example 357: 531.4. Example 358: 534.9. Example 359: 484.9.Example 360: 534.4. Example 361: 564.8. Example 362: 593.0.

Example 363, as shown in Table 1, is made by procedures analogous tothose described below for Example 364. An observed m/z value for thisexample is 422.7.

Example 3642-(6-Ethoxy-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide

4-Methylamino-3-nitro-benzoic acid (25 g) was prepared by followinggeneral procedure A starting from 4-fluoro-3-nitro-benzoic acid (25 g)and 2 M methylamine in THF (100 mL).

4-Methylamino-3-nitro-benzoyl chloride (4.3 g) was prepared startingfrom 4-methylamino-3-nitro-benzoic acid (4 g) in thionyl chloride (20mL). The reaction was heated to 80° C. for 8 h. The solvent wasevaporated to isolate pure compound without any further purification.

(4-Methylamino-3-nitro-benzoylamino)-acetic acid tert-butyl ester (1.2g) was prepared starting from 4-methylamino-3-nitro-benzoyl chloride (1g), amino-acetic acid tert-butyl ester (721 mg), triethylamine (1.4 mL)in DCM (10 mL). The reaction was stirred at 0° C. for 1 h. The reactionwas added to DCM (50 mL) and saturated sodium bicarbonate solution (50mL). The phases were separated, and the aqueous phase was extractedtwice with DCM. The combined organics were dried over sodium sulfate andthen filtered. The solvent was evaporated and crude compound waspurified by flash chromatography using DCM:methanol gradient.

(4-Methylamino-3-nitro-benzoylamino)-acetic acid (800 mg) was preparedstarting from (4-methylamino-3-nitro-benzoylamino)-acetic acidtert-butyl ester (1.2 g) in 4 M HCl-dioxane (2 mL) and DCM (2 mL). Thereaction was stirred at room temperature for 8 h. The solvent wasevaporated to isolate pure compound without any further purification.

N-Dimethylcarbamoylmethyl-4-methylamino-3-nitro-benzamide (800 mg) wasprepared by following General Procedure F starting from(4-methylamino-3-nitro-benzoylamino)-acetic acid (800 mg), 2 Mdimethylamine in THF (3 mL), HBTU (1.5 g), and DIEA (1.3 mL) in DMF (2mL).

3-Amino-N-dimethylcarbamoylmethyl-4-methylamino-benzamide (700 mg) wasprepared by following General Procedure B starting fromN-dimethylcarbamoylmethyl-4-methylamino-3-nitro-benzamide (800 mg) andPd—C (160 mg) in methanol (10 mL).

2-(6-Ethoxy-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide (15 mg) was prepared by followingGeneral Procedure D starting from 6-ethoxy-benzothiazol-2-ylamine (100mg), 3-amino-N-dimethylcarbamoylmethyl-4-methylamino-benzamide (150 mg),thioCDI (150 mg) and EDC (150 mg) in DMF (3 mL). LC/MS: m/z 452.6.

Example 3652-(6-Isopropyl-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide

2-(6-Isopropyl-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide (12 mg) was prepared by followingGeneral Procedure D starting from 6-isopropyl-benzothiazol-2-ylamine(150 mg), 3-amino-N-dimethylcarbamoylmethyl-4-methylamino-benzamide (200mg), thioCDI (200 mg) and EDC (200 mg) in DMF (3 mL). LC/MS: m/z 450.6.

Example 3662-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide (24 mg) was prepared by followingGeneral Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylicacid (80 mg), 2-amino-N, N-dimethyl-acetamide (40 mg), HBTU (95 mg), andDIEA (70 uL) in DMF (1 mL). LC/MS: m/z 486.5. ¹H NMR (DMSO-d₆, 400 MHz):δ 8.57-8.56 (m, 1H), 8.11 (s, 1H), 8.01-8.00 (d, 1H), 7.84-7.82 (m, 1H),7.63-7.61 (d, 1H), 7.57-7.54 (d, 1H), 7.46-7.44 (m, 1H), 4.43-4.40 (t,2H), 4.14-4.13 (d, 2H), 3.75-3.72 (t, 2H), 3.24 (s, 3H), 3.04 (s, 3H),2.87 (s, 3H), —NH proton signal was not observed.

Example 3672-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methylamino-ethyl)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide hydrochloride

4-[2-(tert-Butoxycarbonyl-methyl-amino)-ethylamino]-3-nitro-benzoic acidmethyl ester (1.7 g) was prepared by following General Procedure Astarting from 4-chloro-3-nitro-benzoic acid methyl ester (1 g),(2-amino-ethyl)-methyl-carbamic acid tert-butyl ester (1.2 g) and DIEA(1.7 mL) in THF (20 mL).

3-Amino-4-[2-(tert-butoxycarbonyl-methyl-amino)-ethylamino]-benzoic acidmethyl ester (1.4 g) was prepared by following General Procedure Bstarting from4-[2-(tert-butoxycarbonyl-methyl-amino)-ethylamino]-3-nitro-benzoic acidmethyl ester (1.7 g) and Pd—C (350 mg) in methanol:EtOAc (1:1, 20 mL).

1-[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (1.9 g) was prepared by following General Procedure Dstarting from 6-chloro-benzothiazol-2-ylamine (920 mg),3-amino-4-[2-(tert-butoxycarbonyl-methyl-amino)-ethylamino]-benzoic acidmethyl ester (1.4 g), thioCDI (900 mg) and EDC (960 mg) in DMF (15 mL).

1-[2-(tert-Butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (1.7 g) was prepared by following General Procedure E starting from1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methyl ester (1.9 g) and 2 N NaOH (5 mL) in methanol:THF (1:1, 10mL).

{2-[2-(6-Chloro-benzothiazol-2-ylamino)-5-(dimethylcarbamoylmethyl-carbamoyl)-benzoimidazol-1-yl]-ethyl}-methyl-carbamicacid tert-butyl ester (70 mg) was prepared by following GeneralProcedure F starting from1-[2-(tert-butoxycarbonyl-methyl-amino)-ethyl]-2-(6-chloro-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (146 mg), 2-amino-N,N-dimethyl-acetamide (50 mg), HBTU (125 mg),and DIEA (100 uL) in DMF (1 mL).

2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methylamino-ethyl)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide dihydrochloride (60 mg) was preparedby following General Procedure L starting from{2-[2-(6-chloro-benzothiazol-2-ylamino)-5-(dimethylcarbamoylmethyl-carbamoyl)-benzoimidazol-1-yl]-ethyl}-methyl-carbamicacid tert-butyl ester (70 mg) in 4M HCl in dioxane (1 mL). LC/MS: m/z485.5.

Example 3681-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-1-dimethylcarbamoyl-2-hydroxy-ethyl)-amide

(S)-3-Hydroxy-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid ethyl ester (213 mg) was prepared by following General Procedure Fstarting from1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (200 mg), L-serine ethyl ester hydrochloride (91 mg), HBTU (223mg), and DIEA (128 uL).

(S)-3-Hydroxy-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid (152 mg) was prepared by following General Procedure E startingfrom(S)-3-hydroxy-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid ethyl ester (200 mg) and lithium hydroxide (64 mg).

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-1-dimethylcarbamoyl-2-hydroxy-ethyl)-amide (68 mg) wasprepared by following General Procedure F starting from(S)-3-hydroxy-2-{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid (50 mg), dimethylamine (56 uL, 2 M in THF), HBTU (46 mg), and DIEA(27 uL). LC/MS: m/z 524.0.

Example 3691-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-5-amino-1-dimethylcarbamoyl-pentyl)-amide hydrochloride

(S)-6-tert-Butoxycarbonylamino-2-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-hexanoicacid methyl ester (300 mg) was prepared by following General Procedure Fstarting from1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (392 mg), (S)-2-amino-6-tert-butoxycarbonylamino-hexanoic acidmethyl ester (280 mg), HBTU (400 mg), and DIEA (400 uL) in DMF (2 mL).

(S)-6-tert-Butoxycarbonylamino-2-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-hexanoicacid (260 mg) was prepared by following General Procedure E startingfrom(S)-6-tert-butoxycarbonylamino-2-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-hexanoicacid methyl ester (300 mg) and 2 N NaOH (2 mL) in MeOH:THF (1:1, 2 mL).

[(S)-5-Dimethylcarbamoyl-5-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-pentyl]-carbamicacid tert-butyl ester (200 mg) was prepared by following GeneralProcedure F starting from(S)-6-tert-butoxycarbonylamino-2-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-hexanoicacid (260 mg), 2 M dimethylamine in THF (1 mL), HBTU (400 mg), and DIEA(400 uL) in DMF (2 mL).

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [((S)-5-amino-1-dimethylcarbamoyl-pentylcarbamoyl)-methyl]-amidedihydrochloride (150 mg) was prepared by following General Procedure Lstarting from[(S)-5-dimethylcarbamoyl-5-(2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetylamino)-pentyl]-carbamicacid tert-butyl ester (200 mg) in 4M HCl in dioxane (1 mL) and DCM (2mL). LC/MS: m/z 547.8.

Example 3701-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-5-dimethylamino-1-dimethylcarbamoyl-pentyl)-amide

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid[((S)-5-dimethylamino-1-dimethylcarbamoyl-pentylcarbamoyl)-methyl]-amide(20 mg) was prepared by following General Procedure P starting from1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [((S)-5-amino-1-dimethylcarbamoyl-pentylcarbamoyl)-methyl]-amidedihydrochloride (70 mg), 37% formaldehyde solution (500 uL), andNa(OAc)₃BH (100 mg) in DCM (1 mL) and DMF (500 uL). LC/MS: m/z 575.7.

Examples 371 to 377, as shown in Table 1, are made by proceduresanalogous to those described above for Example 135. Observed m/z valuesfor these examples are as follows. Example 371: 456.6. Example 372:490.6. Example 373: 498.7. Example 374: 532.7. Example 375: 545.5.Example 376: 471.9. Example 377: 526.8.

Example 378, as shown in Table 1, is made by procedures analogous tothose described above for Example 83. An observed m/z value for thisexample is 484.8.

Example 379, as shown in Table 1, is made by procedures analogous tothose described above for Example 135. An observed m/z value for thisexample is 512.7.

Examples 380 to 382, as shown in Table 1, are made by proceduresanalogous to those described below for Example 399. Observed m/z valuesfor these examples are as follows. Example 380: 428.7. Example 381:462.8. Example 382: 473.7.

Example 383, as shown in Table 1, is made by procedures analogous tothose described above for Example 278. An observed m/z value for thisexample is 522.0.

Examples 384 to 386, as shown in Table 1, are made by proceduresanalogous to those described below for Example 399. Observed m/z valuesfor these examples are as follows. Example 384: 485.7. Example 385:499.8. Example 386: 512.8.

Example 387, as shown in Table 1, is made by procedures analogous tothose described above for Example 152. An observed m/z value for thisexample is 498.4.

Example 388, as shown in Table 1, is made by procedures analogous tothose described above for Example 316. An observed m/z value for thisexample is 512.7.

Examples 389 to 393, as shown in Table 1, are made by proceduresanalogous to those described below for Example 399. Observed m/z valuesfor these examples are as follows. Example 389: 570.6. Example 390:524.1. Example 391: 473.7. Example 392: 554.0. Example 393: 513.8.

Example 394, as shown in Table 1, is made by procedures analogous tothose described above for Example 152. An observed m/z value for thisexample is 499.0.

Example 395, as shown in Table 1, is made by procedures analogous tothose described below for Example 399. An observed m/z value for thisexample is 512.7.

Example 396, as shown in Table 1, is made by procedures analogous tothose described above for Example 152. An observed m/z value for thisexample is 513.0.

Examples 397 and 398, as shown in Table 1, are made by proceduresanalogous to those described below for Example 399. Observed m/z valuesfor these examples are as follows. Example 397: 468.5. Example 398:535.7.

Example 3992-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide (102 mg) wasprepared by following General Procedure F starting from{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (100 mg), 3-pyrrolidinol (23 mg), HBTU (109 mg), and DIEA (63 uL).LC/MS: m/z 485.8. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.40 (bs, 1H), 8.54 (q,1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.82 (d, 1H), 7.67 (d, 1H), 7.51 (d,1H), 7.39 (d, 1H), 5.04 (d, 1H), 4.32 (d, 1H), 4.15-3.97 (m, 2H), 3.63(s, 3H), 3.62-3.51 (m, 2H), 3.50-3.33 (m, 2H), 2.05-1.70 (m, 2H).

Examples 400 to 410, as shown in Table 1, are made by proceduresanalogous to those described above for Example 399. Observed m/z valuesfor these examples are as follows. Example 400: 484.7. Example 401:484.7. Example 402: 518.7. Example 403: 518.7. Example 404: 529.8.Example 405: 529.8. Example 406: 549.7. Example 407: 551.8. Example 408:498.7. Example 409: 498.7. Example 410: 532.7.

Examples 411 to 414, as shown in Table 1, are made by proceduresanalogous to those described above for Example 152. Observed m/z valuesfor these examples are as follows. Example 411: 484.5. Example 412:533.4. Example 413: 547.5. Example 414: 547.5.

Example 4151-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((R)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((R)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide (45 mg)was prepared by following General Procedure F starting from{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (95 mg), dimethyl-(R)-pyrrolidin-3-yl-amine (20 mg), HBTU (85 mg),and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 561.4.

Example 4161-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((S)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((S)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide (35 mg)was prepared by following General Procedure F starting from{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (95 mg), dimethyl-(S)-pyrrolidin-3-yl-amine (20 mg), HBTU (85 mg),and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 561.6. ¹H NMR (DMSO-d₆, 400MHz): δ 8.67-8.66 (m, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.84-7.82 (d,1H), 7.66-7.64 (d, 1H), 7.55-7.53 (d, 1H), 7.40-7.37 (d, 1H), 4.09-4.07(m, 3H), 3.86-3.80 (m, 2H), 3.69 (s, 3H), 3.57 (s, 2H), 2.82-2.78 (m,6H), 2.30-2.27 (m, 2H), —NH proton signal was not observed.

Examples 417 and 418, as shown in Table 1, are made by proceduresanalogous to those described above for Example 399. Observed m/z valuesfor these examples are as follows. Example 417: 512.8. Example 418:512.9.

Example 4192-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-((S)-2-dimethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-amide

(S)-1-(2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetyl)-pyrrolidine-2-carboxylicacid methyl ester (114 mg) was prepared by following General Procedure Fstarting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (100 mg), L-proline methyl ester hydrochloride (44 mg), HBTU (109mg), and DIEA (63 uL).

(S)-1-(2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetyl)-pyrrolidine-2-carboxylicacid (54 mg) was prepared by following General Procedure E starting from(S)-1-(2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetyl)-pyrrolidine-2-carboxylicacid methyl ester (90 mg) and lithium hydroxide (29 mg).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-((S)-2-dimethylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethyl]-amide (23mg) was prepared by following General Procedure F starting from(S)-1-(2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetyl)-pyrrolidine-2-carboxylicacid (33 mg), dimethylamine (35 uL, 2 M in THF), HBTU (29 mg), and DIEA(17 uL). LC/MS: m/z 540.7.

Example 420, as shown in Table 1, is made by procedures analogous tothose described above for Example 399. An observed m/z value for thisexample is 535.7.

Example 4212-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-2-oxo-ethyl)-amide

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-2-oxo-ethyl)-amide (75 mg) was prepared byfollowing General Procedure F starting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (100 mg), 2-amino-1-morpholino-1-ethanone hydrochloride (56 mg),HBTU (127 mg), and DIEA (73 uL). LC/MS: m/z 485.7. ¹H NMR (DMSO-d₆, 400MHz): δ 12.38 (bs, 1H), 8.53 (t, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.81(d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.40 (d, 1H), 4.16 (d, 2H), 3.64(s, 3H), 3.63-3.60 (m, 2H), 3.58 (t, 2H), 3.55-3.50 (m, 2H), 3.50-3.45(m, 2H).

Examples 422 to 424, as shown in Table 1, are made by proceduresanalogous to those described above for Example 399. Observed m/z valuesfor these examples are as follows. Example 422: 518.7. Example 423:501.6. Example 424: 533.8.

Example 425, as shown in Table 1, is made by procedures analogous tothose described above for Example 152. An observed m/z value for thisexample is 484.8.

Examples 426 to 430, as shown in Table 1, are made by proceduresanalogous to those described above for Example 399. Observed m/z valuesfor these examples are as follows. Example 426: 498.7. Example 427:531.7. Example 428: 543.8. Example 429: 562.7. Example 430: 591.8.

Example 4311-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide (63 mg) wasprepared by following General Procedure F starting from{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (75 mg), 3-hydroxypiperidine (18 mg), HBTU (73 mg), and DIEA (42uL), with a modification of General Procedure F where DIEA was slowlyadded to the reaction mixture as the last reagent. LC/MS: m/z 549.8. ¹HNMR (DMSO-d₆, 400 MHz): δ 8.53-8.42 (m, 1H), 8.11 (s, 1H), 7.94 (s, 1H),7.79 (d, 1H), 7.66 (bs, 1H), 7.51 (d, 1H), 7.37 (d, 1H), 4.19-4.08 (m,4H), 3.75-3.60 (m, 5H), 3.20 (dd, 1H), 3.05 (t, 1H), 2.01-1.95 (m, 2H),1.57-1.27 (m, 2H), —NH proton signal was not observed.

Examples 432 to 434, as shown in Table 1, are made by proceduresanalogous to those described above for Example 399. Observed m/z valuesfor these examples are as follows. Example 432: 532.7. Example 433:498.7. Example 434: 532.7.

Example 4351-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide (65 mg) wasprepared by following General Procedure F starting from{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (75 mg), 4-hydroxypiperidine (18 mg), HBTU (73 mg), and DIEA (42uL), with a modification of General Procedure F where DIEA was slowlyadded to the reaction mixture as the last reagent. LC/MS: m/z 549.7. ¹HNMR (DMSO-d₆, 400 MHz): δ 8.41 (t, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.80(d, 1H), 7.65 (bs, 1H), 7.51 (d, 1H), 7.37 (d, 1H), 4.15 (d, 2H),3.98-3.89 (m, 2H), 3.78-3.69 (m, 2H), 3.68 (s, 3H), 3.20 (t, 1H), 3.04(t, 1H), 1.84-1.67 (m, 2H), 1.45-1.20 (m, 2H), —NH proton signal was notobserved.

Example 4362-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide

{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid methyl ester (513 mg) was prepared by following General Procedure Fstarting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (500 mg), glycine methyl ester hydrochloride (193 mg), HBTU (634mg), and DIEA (364 uL).

{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (300 mg) was prepared by following General Procedure E startingfrom{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid methyl ester (493 mg) and lithium hydroxide (192 mg).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide (77 mg) wasprepared by following General Procedure F starting from{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (100 mg), 4-hydroxypiperidine (27 mg), HBTU (109 mg), and DIEA (63uL), with a modification of General Procedure F where DIEA was slowlyadded to the reaction mixture as the last reagent. LC/MS: m/z 499.8. ¹HNMR (DMSO-d₆, 400 MHz): δ 8.48 (t, 1H), 8.11 (s, 1H), 7.92 (s, 1H), 7.81(d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.39 (d, 1H), 4.80 (d, 1H), 4.15(d, 2H), 3.98-3.88 (m, 1H), 3.76-3.68 (m, 2H), 3.63 (s, 3H), 3.20 (t,1H), 3.05 (t, 1H), 1.85-1.65 (m, 2H), 1.46-1.20 (m, 2H), —NH protonsignal was not observed.

Examples 437 to 439, as shown in Table 1, are made by proceduresanalogous to those described above for Example 399. Observed m/z valuesfor these examples are as follows. Example 437: 532.6. Example 438:542.9. Example 439: 563.8.

Example 4401-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(3-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(3-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-amide (72 mg) wasprepared by following General Procedure F starting from{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (75 mg), 3-piperidinemethanol (20 mg), HBTU (73 mg), and DIEA (42uL), with a modification of General Procedure F where DIEA was slowlyadded to the reaction mixture as the last reagent. LC/MS: m/z 563.8. ¹HNMR (DMSO-d₆, 400 MHz): δ 12.41 (bs, 1H), 8.53-8.40 (m, 1H), 8.10 (s,1H), 7.93 (s, 1H), 7.87-7.60 (m, 2H), 7.50 (d, 1H), 7.36 (d, 1H),4.73-4.50 (m, 1H), 4.43-4.01 (m, 3H), 3.82 (d, 1H), 3.67 (s, 3H),3.31-3.16 (m, 2H), 3.06-2.87 (m, 1H), 2.86-2.34 (m, 1H), 1.82-1.41 (m,3H), 1.40-1.10 (m, 2H).

Example 4411-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-amide

1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-amide (73 mg) wasprepared by following General Procedure F starting from{[1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (75 mg), 4-piperidinemethanol (20 mg), HBTU (73 mg), and DIEA (42uL), with a modification of General Procedure F where DIEA was slowlyadded to the reaction mixture as the last reagent. LC/MS: m/z 563.8. ¹HNMR (DMSO-d₆, 400 MHz): δ 8.48 (t, 1H), 8.11 (s, 1H), 7.94 (s, 1H), 7.79(d, 1H), 7.67 (bs, 1H), 7.51 (d, 1H), 7.37 (d, 1H), 4.37 (d, 1H), 4.14(d, 2H), 3.92 (d, 1H), 3.67 (s, 3H), 3.27 (d, 2H), 3.02 (t, 1H), 2.58(t, 1H), 1.78-1.55 (m, 3H), 1.20-0.90 (m, 2H), —OH and —NH proton signalwas not observed.

Examples 442 to 444, as shown in Table 1, are made by proceduresanalogous to those described above for Example 399. Observed m/z valuesfor these examples are as follows. Example 442: 514.2. Example 443:557.8. Example 444: 512.8.

Example 4451-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((S)-3-methoxy-piperidin-1-yl)-2-oxo-ethyl]-amide

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((S)-3-methoxy-piperidin-1-yl)-2-oxo-ethyl]-amide (77 mg) wasprepared by following General Procedure F starting from{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (100 mg), (S)-3-methoxy-piperidine hydrochloride (37 mg), HBTU (101mg), and DIEA (58 uL), with a modification of General Procedure F whereDIEA was slowly added to the reaction mixture as the last reagent.LC/MS: m/z 546.7. ¹H NMR (DMSO-d₆, 400 MHz): δ 12.51 (bs, 1H), 8.57-8.47(m, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.89-7.66 (m, 3H), 7.54 (d, 1H),4.33-4.15 (m, 1H), 4.15-4.00 (m, 1H), 3.81-3.56 (m, 4H), 3.55-3.44 (m,1H), 3.43-3.18 (m, 6H), 2.01-1.21 (m, 4H).

Example 4461-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((R)-3-methoxy-piperidin-1-yl)-2-oxo-ethyl]-amide

{[1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid methyl ester (5.0 g) was prepared by following General Procedure Fstarting from1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (5.0 g), glycine methyl ester hydrochloride (1.76 g), HBTU (5.8 g),and DIEA (3.34 mL).

{[1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (4.22 g) was prepared by following General Procedure E startingfrom{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid methyl ester (5.0 g) and lithium hydroxide (1.81 g).

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((R)-3-methoxy-piperidin-1-yl)-2-oxo-ethyl]-amide (30 mg) wasprepared by following General Procedure F starting from{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-aceticacid (80 mg), (R)-3-methoxy-piperidine (100 mg), HBTU (200 mg), and DIEA(100 uL) in DMF (1 mL). LC/MS: m/z 546.7. ¹H NMR (DMSO-d₆, 400 MHz): δ8.54-8.53 (m, 1H), 8.28 (s, 1H), 8.12 (s, 1H), 7.83-7.81 (d, 1H), 7.71(m, 2H), 7.56-7.54 (d, 1H), 4.24-4.18 (m, 1H), 4.12-4.08 (m, 1H),3.73-3.71 (m, 1H), 3.70 (s, 3H), 3.52-3.47 (m, 1H), 3.38-3.34 (m, 2H),3.31-3.25 (m, 4H), 1.88-1.81 (m, 1H), 1.71-1.62 (m, 1H), 1.45-1.36 (m,1H), —NH proton signal was not observed.

Example 447, as shown in Table 1, is made by procedures analogous tothose described above for Example 399. An observed m/z value for thisexample is 576.5.

Example 448, as shown in Table 1, is made by procedures analogous tothose described above for Example 47. An observed m/z value for thisexample is 566.2.

Examples 449 to 452, as shown in Table 1, are made by proceduresanalogous to those described above for Example 399. Observed m/z valuesfor these examples are as follows. Example 449: 600.5. Example 450:557.6. Example 451: 575.5. Example 452: 626.4.

Examples 453 and 454, as shown in Table 1, are made by proceduresanalogous to those described above for Example 152. Observed m/z valuesfor these examples are as follows. Example 453: 561.5. Example 454:513.0.

Examples 455 and 456, as shown in Table 1, are made by proceduresanalogous to those described above for Example 399. Observed m/z valuesfor these examples are as follows. Example 455: 575.4. Example 456:526.7.

Example 457, as shown in Table 1, is made by procedures analogous tothose described above for Example 152. An observed m/z value for thisexample is 526.0.

Examples 458 and 459, as shown in Table 1, are made by proceduresanalogous to those described above for Example 399. Observed m/z valuesfor these examples are as follows. Example 458: 589.5. Example 459:541.0.

Example 460, as shown in Table 1, is made by procedures analogous tothose described above for Example 152. An observed m/z value for thisexample is 526.1.

Example 461, as shown in Table 1, is made by procedures analogous tothose described above for Example 399. An observed m/z value for thisexample is 540.7.

Example 462, as shown in Table 1, is made by procedures analogous tothose described below for Example 463. An observed m/z value for thisexample is 456.7.

Example 4631-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-1-dimethylcarbamoyl-ethyl)-amide

(S)-2-{[1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid methyl ester (863 mg) was prepared by following General Procedure Fstarting from1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (750 mg), L-alanine methyl ester hydrochloride (293 mg), HBTU (870mg), and DIEA (500 uL).

(S)-2-{[1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid (743 mg) was prepared by following General Procedure E startingfrom(S)-2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid methyl ester (850 mg) and lithium hydroxide (299 mg).

1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-1-dimethylcarbamoyl-ethyl)-amide (25 mg) was prepared byfollowing General Procedure F starting from(S)-2-{[1-methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid (100 mg), dimethylamine (119 uL, 2 M in THF), HBTU (98 mg), andDIEA (57 uL), with a modification of General Procedure F where DIEA wasslowly added to the reaction mixture as the last reagent. LC/MS: m/z490.6. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.56 (d, 1H), 8.28 (s, 1H), 8.13 (s,1H), 7.84 (d, 1H), 7.71 (d, 2H), 7.53 (d, 1H), 5.00-4.87 (m, 1H), 3.70(s, 3H), 3.07 (s, 3H), 2.86 (s, 3H), 1.32 (d, 3H), —NH proton signal wasnot observed.

Examples 464 to 468, as shown in Table 1, are made by proceduresanalogous to those described above for Example 463. Observed m/z valuesfor these examples are as follows. Example 464: 511.8. Example 465:498.7. Example 466: 532.7. Example 467: 456.6. Example 468: 490.7.

Example 4692-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [(R)-1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide

(R)-2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid methyl ester (508 mg) was prepared by following General Procedure Fstarting from2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (500 mg), D-alanine methyl ester hydrochloride (214 mg), HBTU (634mg), and DIEA (364 uL).

(R)-2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid (341 mg) was prepared by following General Procedure E startingfrom(R)-2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid methyl ester (475 mg) and lithium hydroxide (180 mg).

2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [(R)-1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide (20mg) was prepared by following General Procedure F starting from(R)-2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-propionicacid (50 mg), 1-methyl-piperazine (50 mg), HBTU (150 mg), and DIEA (100uL) in DMF (1 mL). LC/MS: m/z 511.7. ¹H NMR (DMSO-d₆, 400 MHz): δ8.82-8.67 (m, 1H), 8.12 (m, 1H), 7.97 (s, 1H), 7.85-7.83 (m, 1H),7.56-7.52 (m, 2H), 7.44-7.41 (m, 1H), 5.02-4.96 (m, 1H), 4.50-4.43 (m,1H), 4.35-4.19 (m, 1H), 3.69 (s, 3H), 3.62-3.51 (m, 2H), 3.45 (m, 1H),3.28 (m, 1H), 3.10 (m, 1H), 2.78-2.77 (d, 3H), 1.44-1.35 (m, 3H) —NHproton signal was not observed.

Examples 470 to 472, as shown in Table 1, are made by proceduresanalogous to those described above for Example 463. Observed m/z valuesfor these examples are as follows. Example 470: 545.7. Example 471:498.7. Example 472: 532.7.

For each of the above 472 examples, the invention provides a separateembodiment that includes the free acid or base of the compound andpharmaceutically acceptable salts of the free acid or base. For each ofthese embodiments, the invention provides: (i) a further embodimentwhere the compound is in the form of a free acid or base, and (ii) afurther embodiment where the compound is in the form of apharmaceutically acceptable salt. Any of these embodiments may be usedfor making any of the pharmaceutical compositions described above, andmay also be used in any of the methods of treatment or therapeutic usesdescribed above.

Biological Assay

Cell Culture.

Normal Human Fibroblast (NHLF), were obtained from Lonza. Cultures ofcells were maintained in Fibroblast Growth Medium (FGM-2) mediumsupplemented with 2% fetal bovine serum (FBS), Fibroblast Growth Factor(hFGF-B) 0.5 mL, Insulin 0.5 mL, gentamicin/amphotericin-B 0.5 mL at 37°C. in a humidified atmosphere of 5% CO₂. Cells were grown to 80%confluence before treating.

HMOX1 Protein Assay.

NHLF cells were grown to 80% confluency and harvested by washing oncewith HEPES and then trypsinized. Equal numbers (2×10³ cells per well) ofNHLF cells were plated in 384 well optilux tissue culture (BD) plates.Cells were incubated overnight in FGM-2 medium prior to exposure tocompound. Cells were treated with either vehicle (DMSO) or compound(dissolved in vehicle) for 16 h.

Cells were washed 2× with 1×PBS and fixed with 4% Paraformaldyhyde for15 min.

The fixed cells were then permeablized with 0.1% Triton X-100 andblocked with 5% BSA in 1×PBS 0.05% Tween-20 for 15 min. HO-1 antibody(abcam) was used for immunostaining at 1:300 dilution in 1% BSA in 1×PBSfor 1 hour. Cells were washed 2× with 1×PBS and secondary antibody goatanti-mouse Alexa 488 1:400 dilution (Invitrogen); Hoechst 1:2000(Invitrogen) in 1% BSA in 1×PBS for 1 hour. Plate was washed 5× with1×PBS and read at Hoechst Ex.360 Em. 535; Alexa 488 Ex.480 Em. 535 usingGE InCell 1000. Results analyzed using GE InCell Analyzer software. Hemeoxygenase data represents the fold change above DMSO treated cells.

Table 2, below, shows the fold change above DMSO for Examples 1 to 472.In general, the fold indiction data are reported for 5 μM concentration(i.e., p-moles of compound to total volume, where the solvent is about99.2% media and 0.8% DMSO). In some instances, the reported data are for3 μM concentration, which are indicated by an asterisk (*).

TABLE 2 Example No. HMOX1 Fold Induction 1 19.37 2 6.51 3 12.49 4 11.945 8.33 6 9.45 7 5.40 8 18.32 9 11.16 10 19.89 11 25.0 12 16.16 13 20.0914 22.0 15 22.8 16 30.0 17 21.4 18 20.15 19 21.09 20 18.64 21 19.59 2218.70 23 4.11 24 20.66 25 27.15 26 15.49 27 23.25 28 10.1 29 13.94 3021.43 31 23.57 32 12.64 33 11.65 34 15.44 35 12.36 36 13.8 37 16.4 3818.0 39 18.2 40 11.8 41 33.3 42 34.7 43 29.6 44 12.1 45 12.5 46 17.9 4711.3 48 15.8 49 23.1 50 11.1 51 9.9 52 10.0 53 20.1 54 18.5 55 4.5 5616.1 57 32.0 58 32.8 59 49.8 60 39.8 61 12.1 62 20.3 63 9.8 64 18.9 6510.2 66 20.8 67 18.7 68 21.1 69 4.7 70 21.4 71 4.2 72 11.9 73 20.6 7411.1 75 29.0 76 22.5 77 31.4 78 28.6 79 17.6 80 23.2 81 17.0 82 17.0 831.25 84 19.0 85 11.6 86 9.7 87 12.1 88 13.0 89 23.7 90 8.1 91 10.1 923.4 93 11.3 94 1.2 95 11.2 96 12.0 97 19.2 98 13.8 99 8.5 100 25.9 10111.2 102 22.6 103 9.0 104 16.3 105 17.5 106 23.8 107 18.6 108 18.3 10920.9 110 26.3 111 17.6 112 17.5 113 27.6 114 5.1 115 1.5 116 22.3 11728.8 118 14.1 119 22.1 120 1.7 121 29.6 122 26.1 123 12.7 124 22.9 12525.9 126 4.6 127 12.4 128 32.7 129 31.0 130 5.3 131 6.8 132 5.8 133 45.9134 54.5 135 49.6 136 5.7 137 6.0 138 11.0 139 18.8 140 19.3 141 23.1142 15.2 143 22.4 144 7.3 145 7.1 146 3.7 147 1.8 148 12.0 149 38.7 15041.6 151 41.3 152 15.0 153 4.0 154 27.1 155 24.3 156 21.0 157 22.1 1581.7 159 26.7 160 22.9 161 19.1 162 — 163 26.3 164 20.5 165 17.9 166 22.4167 24.2 168 21.9 169 24.4 170 23.0 171 22.8 172 21.4 173 21.4 174 26.2175 28.7 176 25.8 177 30.3 178 25.7 179 24.4 180 12.4 181 23.0 182 13.0183 — 184 9.5 185 11.2 186 20.2 187 18.4 188 18.3 189 24.6 190 23.4 19133.8 192 28.8 193 11.1 194 6.0 195 4.4 196 11.4 197 18.0 198 12 199 1.5200 22.9 201 26.5 202 15.6 203 18.69* 204 19.33* 205 33.08* 206 27.00*207 11.85* 208 26.50* 209 14.21* 210 29.92* 211 46.15 212 48.81 21348.56 214 42.36 215 16.00* 216 31.60* 217 20.72 218 39.16 219 39.99 22061.89 221 26.00* 222 49.93 223 44.74 224 15.51* 225 17.67* 226 23.32 22714.03* 228 26.00* 229 14.43 230 29.79 231 30.24 232 32.95 233 28.00* 23430.90* 235 37.73 236 45.74 237 30.64 238 33.00 239 10.00* 240 35.42 24123.66 242 28.05* 243 15.23* 244 28.03 245 33.15 246 76.46 247 28.30 24858.71 249 31.19 250 25.12* 251 29.56 252 13.12 253 26.56 254 47.43 25549.33 256 48.00 257 21.87 258 24.65 259 25.35* 260 27.12 261 35.68 26240.00* 263 19.88 264 22.92 265 55.03 266 57.00 267 58.80 268 28.35 26919.94* 270 14.61 271 69.86 272 86.54 273 25.27 274 65.90 275 77.38 27661.20 277 38.27* 278 36.50* 279 89.23 280 38.78 281 35.61 282 51.74 28330.24 284 47.38 285 55.89 286 61.15 287 49.29 288 47.00 289 44.56 29022.54 291 17.04 292 39.03 293 29.39 294 29.42 295 29.00* 296 34.59* 29724.35* 298 21.11 299 16.66 300 26.20 301 27.79 302 63.71 303 25.65 30424.67 305 41.67 306 38.71 307 31.52 308 24.33 309 21.46 310 24.55 31177.35 312 68.84 313 22.90 314 79.73 315 75.66 316 18.15 317 16.33 31811.94 319 23.92 320 20.00 321 15.32* 322 35.99 323 112.89 324 27.89 32532.38 326 34.26 327 31.94 328 29.38 329 52.23 330 37.67 331 70.08 33255.85 333 14.47 334 13.38* 335 18.89 336 16.14 337 12.73* 338 13.58* 33910.63* 340 14.40* 341 32.78* 342 36.81* 343 21.06 344 25.74* 345 26.44*346 12.94* 347 15.34* 348 22.00* 349 29.00* 350 24.00* 351 25.00* 35220.00* 353 23.00* 354 17.00* 355 26.00* 356 19.00* 357 22.00* 358 11.85*359 17.37* 360 34.28 361 28.80 362 13.00 363 10.00 364 27.84* 365 20.05*366 18.79 367 25.41 368 48.03 369 22.41* 370 19.27* 371 28.96* 37225.50* 373 32.01* 374 34.21* 375 19.45* 376 19.09 377 20.33 378 24.92379 21.70 380 29.98* 381 28.17* 382 20.56 383 16.40 384 26.01 385 24.52386 58.28 387 19.90 388 21.98 389 38.56 390 46.35 391 38.65 392 24.86393 61.30 394 37.58 395 72.02 396 36.00 397 25.00* 398 31.70 399 20.83400 15.00* 401 27.00* 402 23.99* 403 24.84* 404 26.14 405 21.37 40631.02 407 7.73 408 25.00* 409 29.00* 410 24.69* 411 16.03 412 47.58 41331.81 414 25.66 415 74.76 416 96.58 417 62.81 418 63.33 419 28.03 42032.96 421 32.19 422 25.01* 423 30.20 424 24.93 425 20.31 426 25.06 42717.02* 428 24.35 429 21.39 430 22.68 431 49.44 432 27.30* 433 29.00* 43434.56* 435 30.22 436 29.26 437 47.08* 438 25.91 439 84.18 440 28.18 44173.59 442 34.92 443 39.76 444 32.00* 445 36.43* 446 31.28* 447 58.35 44836.74 449 22.97 450 51.05* 451 51.29 452 71.66 453 81.11 454 62.24 45580.42 456 67.35 457 39.92 458 68.49 459 41.98 460 27.54 461 27.11 46220.02* 463 26.67* 464 27.17* 465 20.37* 466 22.38* 467 22.31* 468 26.33*469 26.08* 470 24.52* 471 17.36* 472 22.98*

1. A method of treating a disease comprising administering to a humansubject a compound, wherein the disease is a fibrotic disease of thelung, a fibrotic disease of the liver, or a fibrotic disease of theskin; wherein the compound is a compound of Formula (I) or apharmaceutically acceptable salt thereof

wherein one of X¹, X², X³, and X⁴ is

and the remaining members of X¹, X², X³, and X⁴ are independently N or

G is hydrogen, —C₁₋₈ alkyl, —C₃₋₁₀ cycloalkyl, —C₁₋₆ alkylene-C₃₋₁₀cycloaklyl, heterocyclyl, —C₁₋₆ alkylene-C₃₋₁₀ heterocyclyl, phenyl,heteroaryl, or NR^(h)R^(k), where the alkyl, alkylene, cycloalkyl,heterocyclyl, phenyl, and heteroaryl groups are optionally substitutedone or more times with substituents independently selected from R^(c); Lis —CH₂—C(O)N(R⁶)—, —C(O)N(R⁶)—, —C(O)—O—, —SO₂—, —C(O)—, heteroaryleneoptionally substituted one or more times with substituents independentlyselected from R^(x), or heterocyclylene optionally substituted one ormore times with substituents independently selected from R^(x); or thegroup -L-G is -cyano; R¹ is hydrogen, R^(a), phenyl, or heteroaryl,where the phenyl and heteroaryl groups are optionally substituted one ormore times with substituents independently selected from R^(x); R² isR^(b); R³ is hydrogen, —C₁₋₆ alkyl, or —C₁₋₆ alkylene-C₃₋₁₀ cycloaklyl,where the alkyl, alkylene, and cycloalkyl groups are optionallysubstituted one or more times with substituents independently selectedfrom R^(z); R⁴ is —C₁₋₆ alkyl or —C₁₋₆ alkylene-C₃₋₁₀ cycloaklyl, wherethe alkyl, alkylene, and cycloalkyl groups are optionally substitutedone or more times with substituents independently selected from R^(Y);R⁶ is hydrogen, —C₁₋₆ alkyl, —C₁₋₆ alkylene-C₃₋₁₀ cycloaklyl, where thealkyl, alkylene, and cycloalkyl groups are optionally substituted one ormore times with substituents independently selected from R^(x); R^(a) isa) -halogen, b) —C₁₋₆ alkyl, c) —C₃₋₁₀ cycloalkyl, d) -heterocyclyl, e)-cyano, f) —CF₃, g) —OCF₃, h) —O—R^(d), i) —S(O)_(w)—R^(d), j)—S(O)₂O—R^(d), k) —NR^(d)R^(e), l) —C(O)—R^(d), m) —C(O)—O—R^(d), n)—OC(O)—R^(d), o) —C(O)NR^(d)R^(e), p) —C(O)-heterocyclyl, q) —NR^(d)C(O)R^(e), r) —OC(O)NR^(d)R^(e), s) —NR^(d) C(O)OR^(d), or t) —NR^(d)C(O)NR^(d)R^(e), where the alkyl, cycloalkyl, and heterocyclyl groupsare optionally substituted one or more times with substituentsindependently selected from R^(y); R^(b) is a) -halogen, b) —C₁₋₆ alkyl,c) —C₃₋₁₀ cycloalkyl, d) -heterocyclyl, e) -phenyl, f) -heteroaryl, g)-cyano, h) —CF₃, i) —OCF₃, j) —O—R^(f), k) —S(O)_(w)—R^(f), l)—S(O)₂O—R^(f), m) —NR^(f)R^(g), n) —C(O)—R^(f), o) —C(O)—O—R^(f), p)—OC(O)—R^(f), q) —C(O)NR^(f)R^(g), r) —C(O)-heterocyclyl, s) —NRC(O)R^(g), t) —OC(O)NR^(f)R^(g), u) —NR^(f)C(O)OR^(f), or v)—NR^(f)C(O)NR^(f)R^(g), where the alkyl, cycloalkyl, heterocyclyl,phenyl, and heteroaryl groups are optionally substituted one or moretimes with substituents independently selected from R^(Z); R^(c) is a)-halogen, b) —C₁₋₆ alkyl, c) —C₃₋₁₀ cycloalkyl, d) -heterocyclyl, e)-cyano, f) —CF₃, g) —OCF₃, h) —O—R^(h), i) —S(O)_(w)—R^(h), j)—S(O)₂O—R^(h), k) —NR^(h)R^(k), l) —C(O)—R^(h), m) —C(O)—O—R^(h), n)—OC(O)—R^(h), o) —C(O)NR^(h)R^(k), p) —C(O)-heterocyclyl, q)—NR^(h)C(O)R^(k), r) —OC(O)NR^(h)R^(k), s) —NR^(h)C(O)OR^(k), t)—NR^(h)C(O)NR^(h)R^(k), u) —NR^(h) S(O)_(w)R^(k), v) -phenyl, w)-heteroaryl, or x) —O—(C₁₋₄ alkylene)-O—(C₁₋₄alkylene)-N(R^(h))C(O)—OR^(k), where the alkylene, alkyl, cycloalkyl,heterocyclyl, phenyl, and heteroaryl groups are optionally substitutedone or more times with substituents independently selected from R^(x);R^(d) and R^(e) are independently hydrogen, C₁₋₆ alkyl, or C₃₋₁₀cycloalkyl, where the alkyl and cycloalkyl groups are optionallysubstituted one or more times with substituents independently selectedfrom R^(y); or, if R^(d) and R^(e) are both attached to the samenitrogen atom, together with that nitrogen atom may optionally form aheterocyclic ring selected from the group consisting of azetidino,pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino,thiazolidino, isothiazolidino, piperidino, piperazino, morpholino,thiomorpholino, and azepano, where each ring is optionally substitutedone or more times with substituents independently selected from R^(y);R^(f) and R^(g) are independently hydrogen, C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, phenyl, or heteroaryl, where the alkyl, cycloalkyl, phenyl,and heteroaryl groups are optionally substituted one or more times withsubstituents independently selected from R^(z); or, if R^(f) and R^(g)are both attached to the same nitrogen atom, together with that nitrogenatom may optionally form a heterocyclic ring selected from the groupconsisting of azetidino, pyrrolidino, pyrazolidino, imidazolidino,oxazolidino, isoxazolidino, thiazolidino, isothiazolidino, piperidino,piperazino, morpholino, thiomorpholino, and azepano, where each ring isoptionally substituted one or more times with substituents independentlyselected from R^(z); R^(h) and R^(k) are independently hydrogen, C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, heterocyclyl, phenyl, or heteroaryl, where thealkyl, cycloalkyl, heterocyclyl, phenyl, and heteroaryl groups areoptionally substituted one or more times with substituents independentlyselected from R^(x); or, if R^(h) and R^(k) are both attached to thesame nitrogen atom, together with that nitrogen atom may optionally forma heterocyclic ring selected from the group consisting of azetidino,pyrrolidino, pyrazolidino, imidazolidino, oxazolidino, isoxazolidino,thiazolidino, isothiazolidino, piperidino, piperazino, morpholino,thiomorpholino, and azepano, where each ring is optionally substitutedone or more times with substituents independently selected from R^(x);R^(y) is a) -halogen, b) —NH₂, c) -cyano, d) -carboxy, e) -hydroxy, f)-thiol, g) —CF₃, h) —OCF₃, i) —C(O)—NH₂, j) —S(O)₂—NH₂, k) oxo, l) —C₁₋₆alkyl, optionally substituted one or more times with substituentsselected independently from the group consisting of halogen, —OH,—O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂, m)-heterocyclyl optionally substituted one or more times with substituentsselected independently from the group consisting of halogen, —OH,—O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂, n) —C₃₋₁₀cycloalkyl optionally substituted one or more times with substituentsselected independently from the group consisting of halogen, —OH,—O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂, o) —O—C₁₋₆alkyl optionally substituted one or more times with substituentsselected independently from the group consisting of halogen, —OH,—O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂, p) —O—C₃₋₁₀cycloalkyl optionally substituted one or more times with substituentsselected independently from the group consisting of halogen, —OH,—O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂, q) —NH—C₁₋₆alkyl optionally substituted one or more times with substituentsselected independently from the group consisting of halogen, —OH,—O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂, r) —N(C₁₋₆alkyl)₂ optionally substituted one or more times with substituentsselected independently from the group consisting of halogen, —OH,—O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂, s) —C(O)—C₁₋₆alkyl, optionally substituted one or more times with substituentsselected independently from the group consisting of halogen, —OH,—O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂, t)—C(O)—O—C₁₋₆ alkyl, optionally substituted one or more times withsubstituents selected independently from the group consisting ofhalogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,u) —S—C₁₋₆ alkyl, optionally substituted one or more times withsubstituents selected independently from the group consisting ofhalogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,v) —S(O)₂—C₁₋₆ alkyl, optionally substituted one or more times withsubstituents selected independently from the group consisting ofhalogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,w) —C(O)—NH—C₁₋₆ alkyl, optionally substituted one or more times withsubstituents selected independently from the group consisting ofhalogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,x) —C(O)—N(C₁₋₆ alkyl)₂, optionally substituted one or more times withsubstituents selected independently from the group consisting ofhalogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,y) —S(O)₂—NH—C₁₋₆ alkyl, optionally substituted one or more times withsubstituents selected independently from the group consisting ofhalogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,z) —S(O)₂—N(C₁₋₆ alkyl)₂, optionally substituted one or more times withsubstituents selected independently from the group consisting ofhalogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,aa) —NH—C(O)—C₁₋₆ alkyl, optionally substituted one or more times withsubstituents selected independently from the group consisting ofhalogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,or bb) —NH—S(O)₂—C₁₋₆ alkyl, optionally substituted one or more timeswith substituents selected independently from the group consisting ofhalogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂;R^(x) is a) —R^(y) b) -phenyl, optionally substituted one or more timeswith substituents selected independently from the group consisting ofhalogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,c) -heteroaryl, optionally substituted one or more times withsubstituents selected independently from the group consisting ofhalogen, —OH, —O—C₁₋₆ alkyl, —NH₂, —NH—C₁₋₆ alkyl, and —N(C₁₋₆ alkyl)₂,d) —O-phenyl, e) —O-heteroaryl, f) —C(O)-phenyl, g) —C(O)-heteroaryl, h)—C(O)—O-phenyl, or i) —C(O)—O-heteroaryl; R^(z) is a) —R^(y) b) -phenyl,c) -heteroaryl; d) —O-phenyl, e) —O-heteroaryl, f) —C(O)-phenyl, g)—C(O)-heteroaryl, h) —C(O)—O-phenyl, or i) —C(O)—O-heteroaryl; v is aninteger from 0 to 4, and w is an integer from 0 to
 2. 2. The method ofclaim 1, wherein R⁴ is -methyl, -ethyl, -isopropyl, -isobutyl,—CH₂CH₂—OCH₃, —CH₂CH₂—F, —CH₂CH₂—NH₂, or —CH₂CH₂—NH—CH₃; and wherein R³is hydrogen.
 3. The method of claim 2, wherein X³ is

and X¹, X², and X⁴ are each


4. The method of claim 3, wherein v is 1 and R² is attached at the6-position of the benzothiazole ring.
 5. The compound of claim 3,wherein R² is fluoro, chloro, —CF₃, or —OCF₃.
 6. The compound of claim3, wherein R¹ is hydrogen.
 7. The compound of claim 3, wherein R⁴ ismethyl.
 8. The compound of claim 3, wherein L is —C(O)NH—.
 9. Thecompound of claim 3, wherein G is C₁₋₈ alkyl optionally substituted oneor more times with substituents independently selected from R^(c). 10.The compound of claim 9, wherein G is C₁₋₈ alkyl optionally substitutedonce by —C(O)NR^(h)R^(k).
 11. The compound of claim 10, wherein G is—CH₂—C(O)NR^(h)R^(k).
 12. The compound of claim 9, wherein G is C₁₋₈alkyl optionally substituted once by —O—R^(h).
 13. The compound of claim12, wherein G is —(CH₂)₂—OR^(h).
 14. The compound of claim 3, wherein Gis C₃₋₁₀ cycloalkyl optionally substituted one or more times withsubstituents independently selected from R^(c).
 15. The method of claim1, wherein the compound is selected from the group consisting of:1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethyl)-amide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-2-methyl-propyl)-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-hydroxy-ethyl)-amide;2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide;6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ethylamide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-fluoro-ethoxy)-ethyl]-amide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-2-hydroxy-propyl)-amide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((R)-2-hydroxy-propyl)-amide;2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide;1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide;1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-ethoxy-ethyl)-amide;2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (2-fluoro-ethyl)-amide;2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((R)-2-hydroxy-propyl)-amide2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-methoxy-ethoxy)-ethyl]-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-methoxy-ethoxy)-ethyl]-amide; and1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-dimethylamino-ethoxy)-ethyl]-amide; or a pharmaceuticallyacceptable salt thereof.
 16. The method of claim 1, wherein the compoundis selected from the group consisting of:1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-ethyl)-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (3-morpholin-4-yl-3-oxo-propyl)-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((R)-3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-((R)-3-methoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-((S)-3-methoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((S)-3-methoxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((R)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((S)-3-dimethylamino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-2-oxo-ethyl)-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((R)-3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-((S)-3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid [2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-1-methyl-2-morpholin-4-yl-2-oxo-ethyl)-amide; and1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [(R)-1-methyl-2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-amide; or apharmaceutically acceptable salt thereof.
 17. The method of claim 1,wherein the compound is selected from the group consisting of:1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide;2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-dimethylcarbamoyl-ethyl)-amide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-1-dimethylcarbamoyl-ethyl)-amide;2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid (2-dimethylcarbamoyl-ethyl)-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-dimethylcarbamoyl-ethyl)-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid methylcarbamoylmethyl-amide;2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylicacid ((S)-1-dimethylcarbamoyl-ethyl)-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((S)-1-dimethylcarbamoyl-ethyl)-amide; and1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid ((R)-1-dimethylcarbamoyl-ethyl)-amide; or a pharmaceuticallyacceptable salt thereof.
 18. The method of claim 1, wherein the compoundis selected from the group consisting of:1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (2-ethanesulfonyl-ethyl)-amide; and1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid (3-methanesulfonyl-propyl)-amide; or a pharmaceutically acceptablesalt thereof.
 19. A method of treating a disease comprisingadministering to a human subject a compound, wherein the disease is afibrotic disease of the lung, a fibrotic disease of the liver, or afibrotic disease of the skin; and wherein the compound is selected fromthe group consisting of:3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid dimethylcarbamoylmethyl-amide;1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-methoxy-ethyl)-amide;3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (2-methoxy-ethyl)-amide;1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid [2-(2-hydroxy-ethoxy)-ethyl]-amide;6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylicacid (2-morpholin-4-yl-ethyl)-amide;3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylicacid (2-morpholin-4-yl-ethyl)-amide; and1-Methyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylicacid dimethylcarbamoylmethyl-amide; or a pharmaceutically acceptablesalt thereof.
 20. The method of claim 19, wherein the disease is afibrotic disease of the lung selected from the group consisting of COPD,idiopathic pulmonary fibrosis, and sarcoidosis.
 21. The method of claim19, wherein the disease is a fibrotic disease of the liver caused byalcoholic cirrhosis, steatosis, cholestasis, drug side effect, or aviral infection.
 22. The method of claim 19, wherein the disease is afibrotic disease of the skin selected from the group consisting ofscleroderma and psoriasis.